Use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis Citation Yang, Bryant H. (1997) Use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis. Dissertation (Ph.D.), California Institute of Technology. doi:10.7907/1K2S-P110. https://resolver.caltech.edu/CaltechTHESIS:02202014-095838875 Abstract The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is describe. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective a1kylations with a wide range of alkyl halides to afford α-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, and aldehydes. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols. Item Type: Thesis (Dissertation (Ph.D.)) Subject Keywords: pseudoephedrine Degree Grantor: California Institute of Technology Division: Chemistry and Chemical Engineering Major Option: Chemistry Thesis Availability: Public (worldwide access) Research Advisor(s): Myers, Andrew G. Thesis Committee: Dougherty, Dennis A. (chair) Carreira, Erick Moran Barton, Jacqueline K. Myers, Andrew G. Defense Date: 3 March 1997 Non-Caltech Author Email: bryant_yang (AT) yahoo.com Record Number: CaltechTHESIS:02202014-095838875 Persistent URL: https://resolver.caltech.edu/CaltechTHESIS:02202014-095838875 DOI: 10.7907/1K2S-P110 Default Usage Policy: No commercial reproduction, distribution, display or performance rights in this work are provided. ID Code: 8089 Collection: CaltechTHESIS Deposited By: Dan Anguka Deposited On: 24 Feb 2014 22:08 Last Modified: 21 Dec 2019 01:33 Thesis Files Preview PDF - Final Version See Usage Policy. 35MB Repository Staff Only: item control page

Use of Pseudoephedrine as a Practical Chiral Auxiliary for Asymmetric Synthesis Thesis by Bryant H. Yang In Partial Fulfillment of the Requirements for the Degree of Doctor of Philosophy California Institute of Technology Pasadena, California 1997 (Submitted March 3, 1997) 11 © 1997 Bryant H. Yang All Rights Reserved ili Acknowledgments I am indebted to a great many people who were instrumental in the completion of this thesis. Great thanks go to Professor Andy Myers for the professionalism, enthusiasm, advice, and encouragement he provided as my mentor, and for the creativity, knowledge, and scholarship he offered as my research director. I am also grateful for the chance to work on a methodology project which has been challenging and instructive, yet is practical and broadly useful. I know that not everyone gets a second chance, and I feel fortunate for the opportunity I was given. It has been an honor to work alongside a number of talented co-workers. I especially must thank my classmate Tommy Chen, who has worked closely with me for over four years. Apart from his invaluable collaborative assistance, I have also benefited from the good cheer he maintains through even the worst of times, as well as all the times he willingly helped me carry solvents. I benefited from many stimulating discussions with Steve Goldberg during our two plus years of working back-to-back. I also thank Jim Gleason and Mike Kort for being excellent instructors at our problem sessions, and Steve Arvedson for the great times we had both in lab and with CBB. Special thanks also go to former Myers group members Brad, Dave Madar, Shin, Kevin, Pete, Elaine, Nat, Mark, Dave Gin, Marlys, and Susan, as well as to present group members Lydia, Norma, Cindy, Mike, Dave, Dan, Mo and Jun for their advice and friendship over the years. I also thank Erick Carreira and liis research group for many helpful discussions, and Mike Abrams and Professor John Bercaw for providing us with the neopentyllithium used in our studies of LAB. lV Professor Charles L. Perrin was my first organic chemistry professor, and I'm grateful for the chance I had to work in his lab at UCSD. His scholarship and enthusiasm for chemistry remains an inspiration to me. I thank his former students Tammy, John, Kathy, Rich, Miles, Jennifer, Marcey, and Lee. I also thank Erik Sorensen for sharing with me his passion for organic synthesis. This work would not have been completed without the love and support provided by my mother, father, and brother, and so it is to them that I dedicate this work. I thank God for my close friends Chris Lee and Mark Y ee, who were like brothers to me through thick and thin, and for other AACFers Ed, Naoki, Eileen, and Angela for their encouragement that helped me reach this point Finally, I would like to thank the NSF for a predoctoral fellowship. v Abstract The use of pseudoephedrine as a practical chiral auxiliary for asymmetric synthesis is described. Both enantiomers of pseudoephedrine are inexpensive commodity chemicals and can be N-acylated in high yields to form tertiary amides. In the presence of lithium chloride, the enolates of the corresponding pseudoephedrine amides undergo highly diastereoselective alkylations with a wide range of alkyl halides to afford a-substituted products in high yields. These products can then be transformed in a single operation into highly enantiomerically enriched carboxylic acids, alcohols, and aldehydes. Lithium amidotrihydroborate (LAB) is shown to be a powerful reductant for the selective reduction of tertiary amides in general and pseudoephedrine amides in particular to form primary alcohols. vi Table of Contents Acknowledgments ........................................................................... ill Abstract. ...................................................................................... v Table of Contents ............................................................................ vi List of Schemes .............................................................................. ix List of Figures and Tables .................................................................. x List of Abbreviations ........................................................................ xii Chapter 1. Synthesis and Diastereoselective Alkylation of Pseudoephedrine Am ides........... 1 Introduction ........................................................................... 2 Synthesis of Pseudoephedrine Amides ............................................ 8 Alkylation of Pseudoephedrine Amide Enolates .................................. lO Alkylation with Primary Alkyl Halides ..................................... 12 Alkylation with ~-Branched Primary Alkyl Iodides ....................... 15 Concerning Rotamers and Diastereomeric Ratios ......................... 18 Limitations of the Alkylation Methodology ................................ 19 The Basis for Selectivity in Pseudoephedrine Amide Enolate Alky lations ........................................................... 22 Conclusion ............................................................................ 27 Experimental Section ................................................................ 28 vii Chwter 2. Hydrolysis of Pseudoephedrine Amides to Form Highly Enantiomerically Enriched Carboxylic Acids............................................................... 111 Introduction ........................................................................... 112 Basic Hydrolysis of Alkylated Pseudoephedrine Amides to Form Carboxylie Acids ................................................................... 112 Acidic Hydrolysis of Alkylated Pseudoephedrine Amides to Form Carboxylic Acids ................................................................... 115 Hydrolysis of Pseudoephedrine Ami des Involving In Situ BoraneAmine Complexation .............................................................. 116 Experimental Section ................................................................ 120 Chapter3. Reduction of Pseudoephedrine Amides to Form Highly Enantiomerica11y Enriched Primary Alcohols.............................................................. 145 Introduction ........................................................................... 146 Reduction of Pseudoephedrine Ami des with LAB to Form Primary Alcohols .................................................................. 147 Reduction of Tertiary Amides with LAB to Form Primary Alcohols.......... 151 11 B NMR Studies of LAB ........................................................... 153 Reduction of Pseudoephedrine Ami des Involving In Situ BoraneAmine Complexation .............................................................. 154 Conclusion ............................................................................ 156 Experimental Section ................................................................ 157 viii Chapter4. Reduction of Pseudoephedrine Ami des to Form Highly Enantiomerica11y Enriched Aldehydes ....................................................................... 219 Introduction ........................................................................... 220 Reduction of Pseudoephedrine Amides to Form Aldehydes .................... 220 Experimental Section ................................................................ 223 Chapter 5. Synthesis and Diastereoselective Alkylation of C2-Symmetric Bis-amides Derived from Pseudoephedrine and a Dicarboxylic Acid ............................. 237 Synthesis and Alkylation ............................................................ 238 Cleavage of Alkylated C 2-Symmetric Bis-amides ................................ 240 Experimental Section ................................................................ 242 References and Notes .............................................. .. ....................... 262 Appendix. Catalog of Spectra............................................................. 270 1X List of Schemes Schemes Scheme I .............................................................................. ~ Scheme II ............................................................................. 3 Scheme III ............................................................................ 5 Scheme IV ............................................................................ 6 Scheme v ............................................................................. 6 Scheme VI ............................................................................ 14 Scheme VII ........................................................................... ~0 Scheme VIII .......................................................................... 116 Scheme IX ............................................................................ 118 Scheme X ............................................................................. 119 Scheme XI ............................................................................ 155 Scheme XII ........................................................................... 155 X List of Figures and Tables Figures Figure 1. Mnemonic for pseudoephedrine amide enolate alkylation .......... 14 Figure 2. Proposed reactive conformation of pseudoephedrine amide enolates ...................................................................... 23 Figure 3. Crystal structure of pseudoephedrine glycinamide monohydrate ......................................................... 23 Figure 4. Proposed conformations of the lithium enolate of pseudoephedrine propionamide in THF, in the absence of lithium chloride..................... 24 Figure 5. Predicted facial selectivity in the alkylation of structure X with benzyl bromide ............................................................... 26 Figure 6. Sulfuric acid-promoted hydrolysis of pseudoephedrine amides ... 115 Figure 7. Divergent pathways for tertiary amide reductions ................... 146 Figure 8. Generation and cleavage of pseudoephedrine aminals .............. 221 Figure 9. Dieckmann cyclization following the mono-alkylation of pseudoephedrine adipamide ................................................... 239 Tables Table 1. Cost of the Chiral Auxiliaries Prolinol, 2,1 0-Cam phorsultam, 4-Benzyl-2-oxazolidinone, and Pseudoephedrine............................. 4 Table 2. Selective N-Acylation of Pseudoephedrine............................ 8 Table 3. Diastereoselective Alkylation of Pseudoephedrine Amides .......... 13 Table 4. Alkylation of Pseudoephedrine Amides with i)-Branched Electrophiles .......................................................... 16 xi 1 Table 5. H NMR Data for the Lithium Enolate of Pseudoephedrine Propionamide ....................................................................... 26 Table 6. Basic Hydrolysis of Pseudoephedrine Amides ........................ l13 Table 7. Reduction with Borane-Lithium Pyrrolidide (LPT) to Form Primary Alcohols .................................................................. 147 Table 8. Reduction of Pseudoephedrine Am ides with Lithium Amidotrihydroborate to Form Primary Alcohols ............................... 149 Table 9. Use of LAB for the Reduction of Tertiary Amides to Primary Alcohols .................................................................. 152 Table 10. Reduction of Pseudoephedrine Ami des with LiAlH(OEt) 3 to Form Aldehydes .............. .................................................. 220 Table 11. Alkylation of Pseudoephedrine Bis-amides ......................... 239 xii List of Abbreviations Bn benzyl BOC butyloxycarbonyl BOM beniyloxymethyl Bu butyl calcd calculated 'C degrees Celsius CI chemical ionization cm- 1 reciprocal centimeters COSY correlated spectroscopy s chemical shift (parts per million) de diastereomeric excess 2-D two-dimensional DffiAL-H diisobutylaluminum hydride DMAP 4-dimethy laminopyridine DMSO dimethyl sulfoxide E entgegen ee enantiomeric excess EI electron impact ent enantiomer of equiv equivalent(s) EtOAc ethyl acetate FAB fast atom bombardment FfiR Fourier transform infrared g gram(s) GC gas chromatography xiii h hour(s) HPLC high performance liquid chromatography HRMS high resolution mass spectroscopy Hz Hertz i iso J coupling constant L liter(s) IDA lithium diisopropylamide LiTMP lithium 2,2,6,6-tetramethylpiperidide M molar (concentration) (M)+ molecular ion Me methyl mg milligram(s) MHz megahertz min minute(s) mL milliliter(s) mmHg millimeters of mercury mmol millimole(s) mp melting point J.LL microliter(s) mlz mass to charge ratio n normal N normal (concentration) nm nanometers NMR nuclear magnetic resonance NOB nuclear Overhauser enhancement Ph phenyl xiv pH power of hydrogen (concentration) Piv pivaloyl PMA phosphomolybdic acid reagent, 20 wt % solution in ethyl alcohol ppm parts per million Pr propyl R rectus Rf retention factor s sinister SNl nucleophilic substitution, first order t tertiary TBS tert-butyldimethylsilyl TBDPS tert-butyldiphenylsilyl 1FA trifluoroacetic acid THF tetrahydrofuran THP tetrahydropyranyl 1LC thin-layer chromatography uv ultraviolet v/v volume to volume ratio wt% weight percent w/w weight-to-weight ratio z zusammen 1 Chapter 1 Synthesis and Diastereoselective Alkylation of Pseudoephedrine Amides 2 Introduction The asymmetric alkylation of the a-carbon of carboxylic acid derivatives is a reaction of fundamental importance in modem synthetic organic chemistry. 1 With few exceptions, this type of transformation is accomplished using a chiral auxiliary, a molecule that can control the stereochemistry of the alkylation step in such a way as to give product of the desired configuration. For the application at hand, the chiral auxiliary is typically covalently attached to a carboxylic acid equivalent, and once it has achieved its purpose, it is cleaved from the substrate. Because chiral auxiliaries are required in stoichiometric amounts, it is advantageous that they be inexpensive and/or recoverable. In order to be able to access both enantiomers of a given product, it is also useful if both antipodes (or the synthetic equivalent) are readily available. The first practical demonstration of the use of a chiral auxiliary for the asymmetric alkylation of a carboxylic acid enolate equivalent was reported by Meyers and co-workers in 1976.2 In this pioneering work, it was shown that oxazoline anions derived from chiral ~-amino alcohols were alkylated by a range of alkyl halides with high diastereoselectivities Scheme I -LOA 0 HOAyCHs CH2CHs 84% yield, 78% ee 3-6 N HCI 3 (Scheme I). These alkylation products were' then transformed into chiral carboxylic acids with synthetically useful optical purities (51-86% ee). Later, Evans and Takacs3a and Sonnet and Heath3b independently demonstrated that alk:ylations of enolates of tertiary amides derived from the amino alcohol prolinol occurr-ed with higher diastereoselectivities (Scheme II, 76-94% de). Although a limitation of this methodology is the expense of the chiral auxiliary, particularly in the less readily available enantiomeric form (entry 2, Table 1), this work was influential not only as a practical Scheme II Li\ OH 6)LcH, 2 LOA 6:~CHs H jC HCH Br 5 2 OH 0 HO 5 ~CHs : CH 2 C6 H5 92% yield, 74% ee 1 N HCI 100 oc 6lycH 3 CH2 C 6 Hs 75% yield, 76% de addition to synthetic methodology, but also as a paradigm for the design of new chiral auxiliaries employing rigid cyclic platfonns with well defined confonnational preferences. The C2-symmetric bis(methoxymethoxymethyl)pyrrolidine auxiliary of Yamaguchi et al. exemplifies the degree to which this par·adigm has evolved (Scheme III). Alkylation diastereoselectivities of97->98% de ar·e possible with this auxiliary, but a major drawback of this methodology is the difficulty in preparing the chiral auxiliary. From commercial 4 Table 1. Cost of the Chiral Auxiliaries Prolinol, 2,10-Camphorsultam, 4-Benzyl-2oxazolidinone, and Pseudoephedtine entry 1 cost (dollars per gramt cost (dollars per molet (25g) 6.7 677 (Sg) 31.1 3149 (Sg) 23.7 5105 (1 g) 48.2 10378 7.4 1705 9.6 1311 (100 g) 1.0 172 (100 g) 1.2 198 chiral auxiliary (gramst cS: (OH 2 CNH 3 ~· ,NH /?"'o 0 4 "~· HN, o"~'0 0 5 O)l_NH (25 g) L{ CH2CsHs 0 6 O)l_NH (25g) \.......J ··~CH C H 7 ~3 N~H I OH 8 2 6 5 CH3 Qx3 . N~H OH CH3 a Calculated from the price of the largest quantity available from Aldlich Chemical Company, Inc., (1997). materials, the preparation of the auxiliaty requires six linear steps and a resolution. 4 Like the alkylation products of prolinol amide enolate alkylations, difficulties were encountered in transforming the amide alkylation products into useful synthetic inte1mediates. For the 5 latter reason, subsequent developments in chiral auxiliary-based alkylation methodology have focused ptimarily on the alkylation of acyl detivatives that are more readily cleaved than ami des. 5 Scheme III _.....OMOM - 0 ~CH MOMO·"Li. I 3 LOA -78 oc MOMO 0 ~~CHa MOMO !CH3CH2I _.....OMOM 0 = HOAyCH3 CH2CH3 1 N HCI reflux : 0 ~CH ~ 3 CH2CH3 MOMO 79% yield , 99% de An impmtant conttibution in this area is the development of the camphor-detived sultam auxiliaties by Oppolzer and co-workers.6 In addition to the practical feature that the auxiliary can be readily cleaved under mild conditions (Scheme IV), the alkylation reactions are typically highly diastereoselective, and many of the alkylation products are crystalline and are easily emiched to :;:::99% de. Two limitations of this technology are the comparatively high cost of both enantiometic forms of the auxiliary (entlies 3 and 4, Table 1), and the necessity of using the reactivity-enhancing ligand hexamethylphosphmic triamide (HMPA) for efficient alkylation. 6 Scheme IV 23 oc The chiral auxiliaries that have defined the standard in the field for over a decade have been the oxazolidinone auxiliaries of Evans and co-workers. 7 They are commercially available at a reasonable cost (entries 5 and 6, Table 1), their imide derivatives are alkylated with predictable and high diastereoselectivity, and the latter products are readily transfonned into carboxylic acids, esters, and primary alcohols (Scheme V). Scheme V 0 0 OAN~CH \_j ·,,CH2C6Hs 0 3 0 OAN~CH3 W,, CH3 CH2C6Hs 79% yield, >99% isol. de l LiAIH 4 HO~CH3 CH 3 80% yield, >98% ee As a 7 limitation in these alkylation reactions, the oxazolidinone-derived enolates react efficiently only with reactive halides (e.g., allylic halides), and they do not react at all with n-alkyl iodides such as n-butyl iodide. 7b Described herein is the use of the amino alcohol pseudoephedrine as a highly practical chiral auxiliary for asymmetric alkylation reactions. 8•9 Both enantiomers of ~~-H OH CH 3 (S, S)-( +)-pseudoephedrine pseudoephedrine are readily available and are inexpensive (the hydrochloride salt of dpseudoephedtine, for example, is a commodity chemical employed in over-the-counter medications (Sudafed®, Suphedtine®, etc.) with annual worldwide production in excess of 300 metric tons). As is evident from entties 7 and 8 of Table 1, pseudoephedtine is less expensive per gram and per mole than the other commercially available chiral auxiliaries mentioned above. Pseudoephedrine amides are also easily prepared and are frequently crystalline. They undergo efficient and highly diastereoselective alkylation reactions with a wide range of alkyl halides, to include less reactive substrates such as ~-branched alkyl iodides, and these alkylation reactions do not require the presence of carcinogenic cosolvents such as HMP A. Like the starting materials, the alkylated products are frequently crystalline and are easily enriched to ;:::99% de upon recrystallization. The scope of this methodology is defined and possible factors responsible for the exceptionally high levels of diastereoselectivity observed with this nonconventional, acyclic auxiliary discussed. 10 are Extensive developmental work on the transfmmation of the alkylation products into highly enantiometically emiched carboxylic acids, alcohols, and aldehydes is described in subsequent chapters. 8 Synthesis of Pseudoephedrine Amides Amide bond fmmation is one of the most highly developed and efficient transformations in organic chemistry. Acylation reactions of the amino alcohol pseudoephedrine provide no exceptions to this generalization. As shown by the examples of Table 2, pseudoephedtine is acylated in high yield by a vatiety of activated carboxylic acid dedvatives, to include symmettical and mixed anhydiides and carboxylic acid chlorides. 11 •12 Acylation reactions with carboxylic acid anhydrides proceed efficiently in dichloromethane or tetrahydrofuran (THF) as solvent and do not require the presence of an extemal base, although the reactions are much more rapid if a base such as uiethylarnine Table 2. Selective N-Acylation of Pseudoephedrine 0yr' 0 N'H I OH ~R ~,o N~R I CH3 OH cxr CH3 product yield(%) mp (oC) A 1 95b 114-115 n-Bu A 2 91 b 62-63 3 Bn B 3 83b 102-104 4 Ph B 4 88b 145-146 5 i-Pr B 5 92b 73-74 6 t-Bu B CH 2 Bn 8 2-thiophene B Be 88b 81 b 68-69 7 6 7 8 9 3-pyridyl c 9 87 97, 72b 117.5-118.5 10 OH D 10 93 61-63 entry R 1 CH 3 2 method 100-102 110-111 Method A: Acylation with the symmetrical carboxylic acid anhydride (X = RCH 2C0 2). Met11od B: Acylation with the carboxylic acid chloride (X = Cl). Met11od C: Acylation with the mixed anhydride derived from pivaloyl chloride (X= t-BuC0 2). Met110d D: Acylation wit11 t11e met11yl ester (X = CH 30). bValues for products isolated by a single recrystallization of t11e crude product. c Acylation of (1R,2R)-(-)pseudoephedrine. a (1.2 equiv) is added. 9 Acylation reactions with carboxylic acid chlmides require the presence of a slight excess of a base (e.g., Et3N) and occur readily at 0 OC in most organic solvents. 13 In cases where neither the anhydtide nor the acid chlmide derivative of a carboxylic acid is readily available, acylation using the mixed anhydtide fmmed from the carboxylic acid, pivaloyl chlmide, and ttiethylamine is found to be a convenient preparative method (entry 9). Each of the amide products of Table 2 is a non-hydrated, air-stable, free-flowing crystalline solid and can be isolated by direct recrystallization of the crude acylation product (entries 1-7, and 9) or by flash column chromatography (entries 8-10). In most cases, the only by-product in the acylation reactions is a small amount (::;;5%) of the N,O-diacylated product, which is easily separated by recrystallization or flash column chromatography. Because intt·amolecular 0 ~ N acyl transfer within pseudoephedtine ~­ amino esters occurs rapidly, and because theN-acyl fonn is strongly favored under neutt·al or basic conditions, lie products atising from (mono) acylation on oxygen rather than nitrogen, are not observed. The latter feature of pseudoephedrine chemistry makes available yet another procedure for N-acylation that has been developed for a-heteroacetamide derivatives such as pseudoephedrine a-hydroxyacetamide (entry 10, Table 2) and pseudoephedrine glycinamide.14 This procedure takes advantage of the intramolecular 0 ~ N acyl transfer reaction that follows 0-acylation, and employs an a-hetero acetate ester as an 0-acyl transfer agent in the presence of substoichiomettic quantities of a base such as lithium methoxide or n-butyllithium. The fmmation of oligometic by-products is found to be reduced, though not completely suppressed, if the reaction is conducted in the presence of lithium chlmide (2 equiv) as an addition. In the case of entry 10, product yields can be increased by saponifying the crude acylation product with 1 N aqueous sodium hydroxide solution at 23 °C. Under these conditions, the a-hydroxy amide functionality is stable, while the a-hydroxy ester functionalities of the oligometic by-products are saponified. The scope of this reaction methodology has been expanded to include the preparation of 10 8 non-heteroacetamide derivatives, such as pseudoephedtine propionamide. b These reactions proceed optimally using sodium methoxide (0.5 equiv) as base. 8b Alkylation of Pseudoephedrine Amide Enolates Two general procedures for the diastereoselective alkylation of pseudoephedrine amides have been developed. In the first, the alkylation is conducted using excess alkyl halide (procedure A, yield based on enolate), and in the second, excess enolate is used (procedure B, yield based on alkyl halide). Alkylation reactions using the alkyl halide as the limiting reagent are slightly higher yielding than those based on limiting enolate, but the difference is sufficiently minor that the ptimary consideration in choosing a procedure is the expense and/or availability of the alkyl halide relative to that of the pseudoephedrine amide. In a typical protocol employing excess alkylating agent (procedure A), a suspension of anhydrous lithium chlmide (6.0-7.0 equiv) in THF containing diisopropylamine (2.25 equiv) is treated at -78 OC with a solution of n-butyllithium in hexanes (2.1 equiv). The resulting suspension is held at -78 OC for 5 min, the reaction flask is briefly transfetTed to an ice bath (5 min), then is cooled to -78 °C. A solution of the pseudoephedtine amide substrate (1 equiv) in THF is added to the cold suspension of lithium diisopropylamide-lithium chlmide and the mixture is held at -78 oc for 30-60 min, then is warmed to 0 OC and is held at that temperature for 10-15 min. The enolate suspension is stirred btiefly at 23 OC (3-5 min), then is cooled to 0 OC and is treated with an alkylating agent (1.5-4.0 equiv). For most substrates, enolization is rapid at 0 OC and further watming to 23 OC is probably unnecessary, although innocuous, because pseudoephedrine amide enolates generally exhibit good thetmal stability at 23 OC (tlf2 > 12 h). Reactions employing excess enolate (procedure B) are conducted similarly, but with 1.3-1.8 equiv of enolate and 1 equiv of electrophile. It is important in these reactions 11 that excess base (LDA) not be used, for many electrophiles are destroyed by the excess base. Typically, we employ 1.90-1.95 moles of LDA per mole of amide substrate in reactions with excess enolate. The presence of lithium chloride in the reaction is essential to accelerate the rate of alkylation. In addition, 0-alk:ylation of the secondary hydroxyl group of the pseudoephedrine auxiliary is suppressed in the presence of lithium chloride. At the concentrations of a typical alkylation reaction (-0.2 M in enolate), the solubility limit of lithium chloride is reached at approximately 5 equiv at 0 0C and 6 equiv at 23 °C. Thus, typical reactions conducted with the recommended 6.0-7.0 equiv of lithium chloride are saturated; use of more than 7 equiv of lithium chloride in the reaction produces no discemible differences in the reaction rate, yield, or diastereoselectivity. Alkylation reactions conducted in the presence of fewer than -4 equiv of lithium chloride are markedly slower and typically do not proceed to completion. For example, in the absence of lithium chlmide, the reaction of n-butyl iodide with the enolate derived from pseudoephedrine propionamide proceeds to the extent of only 32% within 5 h at 0 °C, whereas in the presence of 6 equiv of lithium chloride the alkylation reaction is complete within 1.5 h at 0 °C (80% yield of recrystallized product). Trapping of the same enolate with benzyl bromide proceeds to only 60% completion in the absence of lithium chloride, but affords a 90% yield of recrystallized product in its presence (6 equiv). In neither case was the diastereoselectivity of the alkylation reaction influenced by the presence of lithium chlmide in the medium. 15 It is important to ensure that rigorously anhydrous lithium chlmide is employed in the alkylation reaction, for any water of hydration will quench the strong base used in the enolization step. It is recommended that the (highly hygroscopic) anhydrous reagent be flame-dried immediately prior to use followed by cooling under an inert atmosphere at 23 oc. 12 The role of lithium chloride in the reaction is not known. There is ample precedent in the literature, notably in the work of Seebach and co-workers, documenting the beneficial influence of lithium chl01ide in enolate alkylation reactions. It has been proposed in these studies that lithium chlodde may modify the aggregation state, and thereby the reactivity of an enolate in solution.16 Alkylation with Primary Alkyl Halides. react efficiently (80-99% yields of purified Pseudoephedtine amide enolates alkylation products) and highly diastereoselectively (94-98% cmde de, 95-2::99% isolated de) with a wide variety of primary alkyl halides (Table 3). Each of the examples in Table 3 involves a readily available and/or inexpensive alkyl halide and therefore was conducted with limiting enolate (procedure A). Because pseudoephedtine amide enolates are highly nucleophilic, many ptimary alkyl halides react readily even at -78 OC (e.g., entries 8 and 11). Reactions conducted at -78 OC display slightly enhanced diastereoselectivities versus the same reactions conducted at 0 OC (entries 7 and 10), but reactions conducted at 0 OC are nevertheless highly diastereoselective. Notably, even poorly reactive substrates such as nalkyl iodides (entries 2, 5, and 9) react efficiently and highly selectively with pseudoephedrine amide enolates at 0 °C. 17 Elimination-prone substrates such as (2- iodoethyl)benzene (entry 5) react efficiently, showing little evidence of elimination. Similarly, the potentially enolizable substrate tert-butyl bromoacetate (entry 6) is found to alkylate the enolate derived from pseudoephedrine propionamide in good yield. The electr·ophile benzyloxymethyl chl01ide (BOM chloride, entry 3) is singular in that it is found to alkylate pseudoephedrine amide enolates with poor diastereoselectivity (33% de). This poor selectivity is thus far unique to this substrate and may reflect a change in the reaction mechanism, perhaps toward an SN1-type transition state. The use of BOM bromide as substrate (entry 4) obviates this problem, returning the high diastereoselectivity found with all other alkyl halides used in this study. In every case studied, the major 13 Table 3. Diastereoselective Alkylation of Pseudoephedtine Amides 1) LDA, LiCI 2) R'X Entry R R'Xa temp prod. (OC) cmde de isol de isol yield mp (%) (% ) (%) (OC) 1 CH 3 BnBr 0 11 94 299b 90b 136-137 2 CH 3 n-Bul 0 12 98 299b 80b 66-67 3 4 CH 3 CH 3 BOMCl BOMBr 0 -78 13 13 33 98 33 98 77 80 65-66 5 6 CH 3 CH 3 Bn Bn Bn n-Bu C 6 H 5 (CH 2 ) 21 BrCH2CO/-Bu CH 31 CH 31 n-Bul CH 31 0 - 78 14 16 -78 0 0 16 18 95 96 94 97 98 94 86 78 0 95 94 94 97 98 94 90 94 18 19 96 98 96 89 299b 87b 120-121 96 95 299 299b 92 92c 65-66 89-90 299b 83b 23 98 98 299b 84b 118-119 125-127 24 98 98 83 109-110 25 95 95 88 7 8 9 10 15 17 11 12 ~Bu CH~ n-Bu BnBr -78 0 13 Ph Etl 0 20 14 CH 2Bn CH 31 0 21 0 0 -78 -78 22 15 16 17 18 i-Pr BnBr t-Bu BnBr 3-pyridyl CH 2 =CHCH 21 2-thiophened CH 31 99 95 79-81 79-81 a All reactions were conducted with excess alkyl halide (1.5-4.0 equiv). b Values for products isolated by a single recrystallization of the crude reaction mixture. cTwo recrystallizations were conducted. d Alkylation of (1R,2R)-pseudoephedrine-2-thiopheneacetamide. product arises from electrophilic attack on the putative Z-enolate (R syn to the enolate oxygen) from the same face (1,4-syn) as the carbon-bound methyl group of the pseudoephedrine auxiliary when the enolate is drawn in a planar, extended confonnation (see Figure 1). 14 --- 1,4-syn R'-X Figure 1. Mnemonic for pseudoephedrine amide enolate alkylation. A particularly valuable feature of pseudoephedrine as a chiral auxiliary from the standpoint of process chemistry is the crystallinity of its N-acyl derivatives; many of the alkylation products are crystalline materials and can be isolated in ~99% de and >80% yield after recrystallization of the crude reaction products (entries 1-2, 12, and 14-16). Typically, at least one diastereomer within a given diastereomeric pair of alkylation products is crystalline. Thus, by proper choice of theN-acyl group, alkyl halide, and the configuration of the pseudoephedrine auxiliary (d or 1), a crystalline product can often be Scheme VI ~ ! ! ~H30 Qf30 ~~~CH3 OH CH3 CH3 .o ~ ~~CH3 OH 12 mp 66-67 oc \ I 0 HO~CH3 CH 3 40 CH3 CH3 ent-18 (oil) 15 obtained. For example, (R)-2-methylhexanoic acid 40 is obtained by the hydrolysis of either diastereomer 12 or ent-18; however, only 12 is crystalline (Scheme VI). To obtain (R)-2-methylhexanoic acid from the crystalline intetmediate 12, (S,S)-pseudoephedrine propionamide is alkylated with n-butyl iodide, followed by hydrolysis (vide infra) of the product 12. Alkylation with 13-Branched Primary Alkyl Iodides. The superior nucleophilicity and excellent thetmal stability of pseudoephedtine amide enolates make possible alkylation reactions at 23 OC with ordinarily unreactive substrates such as 13branched primary alkyl iodides. This is a valuable transfonnation for it provides a concise route to "skipped" or 1,3-dialkyl-substituted carbon chains, found within many natural products. With chirall3-branched primary iodides, an important issue concerns the degree to which the existing stereocenter within the electrophile will influence the stereoselectivity of the alkylation reaction. In initial studies, the alkylation of both enantiomers of pseudoephedrine propionamide with (S)-1-iodo-2-methylbutane was examined. Each reaction was conducted using excess enolate (1.8 equiv) 18 and limiting alkyl iodide (procedure B). As shown by entties 2 and 3 of Table 4, both alkylation reactions were highly selective and efficient, although that producing the 1,3-syn product (entry 3) proceeded with slightly higher diastereoselectivity, suggesting that this represents a "matched" case. These and other findings within Table 4 represent significant advances over existing asymmetlic alkylation methodology. For example, alkylation of the enolate derived from (S)-prolinol propionamide with (S)-1-iodo-2-methylbutane in the presence of HMPA is reported to proceed in 49% yield and 90% de. 19 In addition, the selectivity of the latter reaction was found to be reduced on larger scale (-80% de, 10 mmol). 19a By contt·ast, in no case have we observed a variation in product de as a function of scale in the alkylation of a pseudoephed1ine amide enolate. 20 methodology 21 Use of Enders' chiral hydrazone in the synthesis of 1,3-dimethyl-substituted carbon chains has been 16 Table 4. Alkylation of Pseudoephedrine Am ides with ~-Branched Electrophiles X~CH3 ljf entty Ria 0 0 LOA, LiCI; Rl THF, 23 oc x'VJYR CH3 A + product time (h) x'VJlyR CH3 B isol yield ratio of A:B (%) 0 1 I~CHa 6 !-yycHa X.., 89 86: 1 94 62: 1 94 1: 89 97 >99: 1 95 1:58 93 142: 1 96 1:70 93 66: 1 94 1: 199 CH3 CH3 CHa 26 0 2 I~CHa 20 x..,~cH 3 CH 3 CH3 CHa 27 0 3 I~CH 3 18 ~ : .: CH3 X, - CHa CHa CHa 28 0 4 I~ Ph 6 x,~Ph CH 3 CH 3 CHa 67 29 0 5 I~ Ph 7 x..,~Ph CH 3 CH 3 CH3 67 30 0 6 ~Ph 18 x..,~Ph CH3 CH3 CH3 CH3 CH3 68 31 0 7 ~Ph 18 x,~Ph CH3 CH3 CH3 CH3 CH3 68 32 0 8 I~ Ph 12 x,~Ph CHa CH3 CH3 CH3 CH3 69 33 0 9 a I~ Ph 18 x~Ph CH3 CH3 CH3 CH3 CH3 69 34 Except in entry 1 where 4 equiv of iodide were used (yield based on pseudoephedrine runide), and the alkylation was conducted at 0 °C, all alkylations were conducted at 23 oc using excess enolate (1.8-2.0 equiv, yield based on all...J'l iodide). 17 successfully implemented by Nicolaou et al. 22 in their synthesis of the sidechain of zaragozic acid A, but the expense of the auxiliary makes the large-scale applications of this methodology impractical. Similarly, use of Evans' chiral imide enolate methodology7 in the synthesis of 1,3-dimethyl-substituted fragments was described recently by Decicco and Grover in synthetic studies of microcolin A, but the alkylation required the use of a large excess (25 equiv) of the alkylating agent. 23 This is an undesirable feature in any reaction, but particularly in an iterative sequence (vide infra) where the electrophilic component becomes successively more valuable with each iteration. In their asymmetlic synthesis of ionomycin, Evans et al. pointed out that a sequence involving the asymmetric alkylation of a chiral propionate-delived enolate, reduction of the alkylation product to a primary alcohol and alcohol activation (e.g., RCH2 0H ~ RCH 2 1), followed by a second alkylation reaction with a chiral propionatedelived enolate would provide an iterable approach to the synthesis of 1,3,5,n-polymethylsubstituted chains. 24 This strategy was adopted in order to illustrate the application of pseudoephedline amide enolate alkylation chemist:Iy to the iterative synthesis of 1,3,5,n(odd)-polymethyl-substituted cm·bon chains of any configuration, and results are shown in Table 4. 25 Thus, tl-eatment of the iodide 67 26 with 1.8 equiv of the enolate derived from (S,S)-pseudoephedrine propionamide (1) at 23 0C for 6 h afforded the 1,3syn alkylation product 29 with >99: 1 diastereoselectivity and in 97% yield whereas use of the enolate delived from (R,R)-pseudoephedtine propionamide (ent-1) under identical conditions provided the 1,3-anti product 30 with 58:1 diastereoselectivity and in 95% yield 18 27 (entries 4 and 5). ' As before, the reaction producing the syn stereochemistty appears to represent a matched case while that producing the anti diastereomer represents a mismatched case, although even the mismatched alkylation reaction is highly selective. Alkylation products 29 and 30 were transfonned into the corresponding alcohols by LAB reduction (vide infra), and then to the COlTesponding iodides in an aggregate yield in excess of 91%. Iodides 68 and 69 were felt to provide a more stringent test of 18 secondary diastereodifferentiating effects in the alkylation reactions. Reaction of the syn iodide 68 (1 equiv) with 1.8 equiv of the enolate detived from 1 afforded the syn,syn alkylation product 31 with 142:1 selectivity and in 93% yield, whereas the enolate delived from ent-1 produced the anti,syn product 32 with only slightly lower selectivity (70: 1, 96% yield). Reaction of the anti iodide 69 with 1.8 equiv of the enolate detived from 1 produced the anti,anti amide 33 with 66:1 selectivity and in 93% yield, whereas the alkylation of the enolate delived from ent-1 proceeded with higher selectivity (199:1) to form the syn,anti product 34 in 94% yield. These results again support the idea that 1,3syn products represent matched cases and demonstrate convincingly that the high diastereofacial bias of pseudoephedrine amide enolates ovenides secondary effects due to the stereocenter within the alkyl iodide. The diastereoselectivities of the alkylation reactions can be seen to increase with the ste1ic bulk of the alkyl iodide. In addition, the results of Table 4 illustrate the exceptional efticiency of the alkylation reactions when limiting iodide is employed (procedure B), with chemical yields typically exceeding 93%. Concerning Rotamers and Diastereomeric Ratios. Like most te1tiary amides, pseudoephedrine amides exhibit rotational isometism about the N-C(O) bond and interconversion of isomers is slow on the NMR ('H and 13 C) time scale. In one case (substrate 11), we observed a coalescence temperature of 120 OC: ('H NMR at 400 MHz, DMSO) for rotamer interconversion. In solution, the ratio of rotational isomers of pseudoephedrine am ides typically varies from 1:1 to 7:1. In all cases, the major rotamer in solution is assigned as that with theN-methyl group anti to the carbonyl group on the basis of its shielding relative to the minor isomer. 28 Interestingly, in solid state stmctures of three pseudoephedrine amides (11, 12, and 16 below) 8 a single rotameric f01m is present wherein theN-methyl group is syn to the carbonyl group, the minor isomer in solution. However, in a fomth stmcture (pseudoephedrine glycinamide monohydrate, vide infra) 14 19 11 12 16 the amide crystallized exclusively as the rotamer with theN-methyl group anti to the amide carbonyl. These data reveal the fine balance in energetics between isomers, and the importance of crystal packing forces on the distribution. From a practical standpoint, the 1H NMR spectrum of a given pseudoephedrine amide will be complicated by the presence of rotamers and for this reason diastereometic ratios are best assigned by capillaty GC analysis. Typically, the corresponding trimethylsilyl ether or acetate ester is prepared and analyzed using a Chirasil Val column (Alltech). Limitations of the Alkylation Methodology. In testing the limits of pseudoephedrine amide enolate alkylations, we have found that the alkylation of pseudoephedtine amide enolates with secondary alkyl halides such as cyclohexyl bromide and cyclohexyl iodide is exceedingly slow and does not provide a viable route to products of this type. 29 Another problematic case we have encountered is the alkylation of pseudoephedrine a.-hydroxyacetamide 10 and its protected delivatives. Enolization of 10 using 3.2 equiv of LDA at -78 °C was accompanied by partial decomposition of the statting matelial. By using excess pseudoephedrine a.-hydroxyacetamide (1.65 equiv) and limiting benzyl bromide the C-alkylated product 35 was formed in 84% yield and 82% de. This diastereo- 20 10 selectivity is lower than that obtained in benzylations of other pseudoephedrine amide enolates, including the a-heterosubstituted enolates derived from pseudoephedrine glycinamide,9 chloroacetamide, 8 and fluoroacetamide 30 and may be related to the fact that the pseudoephedrine a-hydroxyacetamide enolate is a presumed trianion whereas the latter enolates are all dianions. Alkylation reactions of an extensive series of 0-protected derivatives of pseudoephedrine a-hydroxyacetamide were also examined, but the alkylation reactions were either unselective (protecting group = TBS, TBDPS, THP, BOM, Piv, and methyl-1-methoxyethyl), or the enolate was unstable (protecting group = Bn). Consequently, none of these offered any improvement over pseudoephedrine a- hydroxyacetamide itself. We also encountered difficulties when we attempted to extend our alkylation studies to pseudoephedrine crotonamide (36). It was anticipated that alkylation of the lithium enolate of 36 with a suitable electrophile (E+) would occur at the a position to yield a p,y-unsaturated amide (Scheme VII). When amide 36 was subjected to standard enolization conditions (LDA, LiCl, THF), followed by quenching with benzyl bromide at Scheme VII H3 0 N~CH 3 I OH CH3 36 - base Oli x~CH2 "' - 21 0 °C, a substantial (>50%) quantity of a by-product adsing from the 1,4-conjugate addition product of LDA with pseudoepheddne crotonamide was isolated (4: 1 ratio of diastereomers). Although the desired f3,y-unsaturated alkylation product (37) could be LOA, LiCI 4:1 ratio of diastereomers recovered from the reaction mixture, it was contaminated with an approximately equal quantity of the a.,(3-unsaturated isomer 38. Presumably, the (3,y-unsaturated amide is the kinetic alkylation product, but it undergoes base-cataly:zed isomedzation at 0 OC to afford the corresponding a.,(3-unsaturated isomer. 0 0 0 H ~ CH2 + xJY'-cHa X~CHa LOA, LiCI; PhCH2Br X'l'+~ THF, 0 oc CH2Ph CH2Ph 37 38 36 Use of the more hindered base lithium 2,2,6,6-tetramethylpiperidide (LiTMP) gave reduced yields of the corresponding conjugate addition by-product, though a minor amount of a dimeric product, resulting from conjugate addition of the pseudoephedrine crotonamide enolate with unreacted pseudoephedtine crotonamide (or its alkoxide), was also detected. Optimal results were achieved when an ice-cooled solution of pseudoepheddne crotonamide in tetrahydrofuran was added to a suspension of LiTMP and lithium chloride in tetrahydrofuran at 0 °C. At 0 OC the enolization of pseudoepheddne crotonamide is thought to be nearly instantaneous, thus the conjugate addition of pseudoephedrine crotonamide enolate with unreacted pseudoephedtine crotonamide does not occur. The enolate was then cooled to -78 OC (a necessary modification to prevent 22 double bond migration following the alkylation step), and benzyl bromide was added. The reaction mixture was stirred for 2 hours at -78 °C, and afforded a 72% yield of the desired product 37 after purification by flash column chromatography, with none of the a.,~­ unsaturated compound 38. The crude de was 93%, and the minor diastereomer could be removed efficiently by recrystallizing the chromatographed material from ethyl acetate. ~H 3 ~ ~ . ~N~CH OH CH3 LiTMP, LiCI;PhCH2 Br; 3 THF, -78 oc 36 37: 72% yield , 93% de One limitation about can-ying out the alkylation reaction at -78 OC is that pseudoephedrine amide enolate alkylations do not proceed efficiently at -78 OC with less reactive electrophiles, such as 1-iodobutane. The alkylation reaction with 1-iodobutane at -78 °C proceeds in only 33% yield, but in 97% de. The Basis for Selectivity in Pseudoephedrine Amide Enolate Alkylations. In an effort to obtain stmctural information conceming the confmmations of pseudoephedrine amide enolates, we attempted to crystallize a pseudoephedrine amide enolate. Despite extensive effmts over a wide range of pseudoephedrine amide substrates (e.g., pseudoephedrine propionamide, chloroacetamide, 8 phenylacetamide, and the c2 symmetric bis-amides, vide infra), in no case have we been successful in obtaining an Xray quality crystal of a pseudoephedrine amide enolate. The stmctural similarity between pseudoephedrine amides and prolinol amides (both are amides of 2-amino alcohols) and the observation that, in both systems, alkyl halides and epoxides exhibit opposite diastereoselectivity in alkylation reactions 31 ' 32 suggest that the migin of selectivity in the two systems may be similar. Askin et al. have suggested that tl1e alkoxy group of prolinol amide enolates may direct tl1e alkylation reaction in the case of epoxide electrophiles, and provide a steric blockade in reactions with 23 alkyl halides. 32 A similar rationale may explain the selectivity of pseudoephedrine amide enolate alkylations if a reactive confmmer such as that shown in Figure 2 is invoked. In this conformation, the lithium alkoxide, and perhaps more importantly, the solvent Alkyl Halides Figure 2. Proposed reactive conformation of pseudoephedrine amide enolates. molecules (tetrahydrofuran and possibly diisopropylamine) associated with the lithium cation are proposed to block the ~-face of the Z-enolate, forcing the alkylation to occur from the a-face. In this model, the pseudoephedrine side chain adopts a staggered conformation in which the C-H bond a to nitrogen lies in-plane with the enolate oxygen, in accord with predictions based on allylic strain arguments. 33 The positioning of tl1e secondary alkoxide on the ~-face of the enolate may also benefit from extended coordination of the oxyanions witl1 one or more lithium cations. The feasibility of such a Figure 3. Crystal stmcture of pseudoephedrine glycinamide monohydrate. 24 staggered conformer is supported by a similar conformer depicted in the X-ray crystal structure of pseudoephedrine glycinamide monohydrate (Figure 3 ), 14 wherein allylic and torsional strain is minimized, and the secondary hydroxyl group is disposed on the ~-face of the plane defined by the amide bond linkage. Although the proposed model provides a rationale for the observed selectivity, it should be noted that several important features of the actual transition structure of the enolate have been neglected such as its aggregation state, rotameric distribution, state of ionization, and the degree of pyramidalization of nitrogen, as well as the bond-breaking and bond-forming trajectmies. Attempts to con·oborate the proposed structure in Figure 2 with 1H NMR data have been complicated by poor line shape or highly complex spectra. When the lithium enolate of pseudoephedrine propionamide is generated in the presence of lithium chlmide, the 1H NMR spectrum in THF-d8 shows a single species, but the signals are too broad to allow for the determination of any coupling constants, or to conduct any NOE (nuclear Overhauser enhancement) studies. When the enolate is generated in the absence of lithium chloride, the 1H NMR spectrum shows two separate species with sharply defined signals. Through 2-D con·elated spectroscopy (COSY) studies and differential NOE measurements, we were able to assign each peak to its respective structure and to assign a reasonable confmmation to each structure (structure X and structure Y, Figure 4). 34 Figure 4. structure X structure Y J (Ha-Hb) = 8.0 Hz J (Ha-Hb) = 0 Hz 8 (Mec): 0.60 ppm 8 (Meb): 1.82 ppm Proposed confmmations of the lithium enolate of pseudoephedrine propionamide in THF, in the absence of lithium chloride. 25 For structure X, the NOE between protons of the N-methyl group (M{\) and the enolate proton (He) establishes the enolate is of the Z-configuration and is in the anti conformer (N-methyl group is anti to the enolate oxygen). The 8.0 Hz coupling constant between Ha and Hb is consistent with a dihedral angle of 150° to 180° or 0° to 20°,35 but the NOE between the protons of theN-methyl group (M{\) and Hb virtually rules out the latter possibility. The steric interaction between the phenyl ring and Mec can be minimized by turning the face of the aromatic ring toward Mec, which may explain the upfield shift (3 = 0.60 ppm) for the protons of Mec. It is interesting to note that the conformer of structure X is essentially that shown in Figure 2 for R =Me. As drawn, the oxyanions of structure X are in close proximity, and thus an extended coordination of the oxyanions with one or more lithium cations is possible. Structure Y also displays an NOE between protons of the N-methyl group (M{\) and the enolate proton (HJ, suggesting that structure Y is a Z-enolate, and that the Nmethyl group is anti to the enolate oxygen. However, the absence of coupling between Ha and Hb, and an upfield shift of the N-methyl group (M{\) protons suggest the structure shown above. The 1,3-diaxial interaction between the phenyl ring and theN-methyl group can be minimized by turning the face of the aromatic ring toward the N-methyl group, which would explain the upfield shift for Meb (3 = 1.82, cf. 3 = 2.52 for structure X). A comparison of the chemical shifts of structure X and structure Y with that of the enolate generated in the presence of lithium chloride (structure Z) suggests that structure Z may be similar to that of structure X, and hence, to the conformer proposed in Figure 2 (Table 5). In all cases, the chemical shifts of structure Z resemble those of structure X more closely than those of structure Y. In particular, the upfield shift of Mec in structure Z suggests that the phenyl ring is opening its face to Mec, as in structure X. It is not clear at present why the selectivity of the asymmetric alkylation reaction is relatively unaffected by the concentration of lithium chloride. In the absence of lithium 26 1 Table 5. H NMR Data for the Lithium Enolate of Pseudoephedrine Propionamide Ha MecOLi PhyzNAyMea Hb' Oli Meb He resonance structure X (8) structure Y (8) structure Z (8) Ha 3.50 2.96 too broad to find Hb 4.56 4.83 4.4 He 3.34 3.19 3.3 Mea 1.43 1.28 1.45 Met, 2.52 1.82 2.35 Mec 0.60 1.70 0.4 chloride, structure X and structure Y are present in equimolar amounts. While it would be expected that the alkylation of structure X will occur almost exclusively from the front face to afford the observed product (Figure 5), both of the enolate 1t-faces of structure Y appear to be accessible. It is possible that in the absence of lithium chloride, structure Y is in an unreactive aggregation state. OH CH3 CH2Ph A1JyNJMe CH3 ~ 11 Figure 5. bromide. Predicted facial selectivity in the alkylation of structure X with benzyl In the context of this discussion of the diastereoselectivity of pseudoephedrine amide enolate alk:ylations, it is interesting to note that the use of ephedrine, the diastereomer of pseudoephedrine, as a chiral auxiliary in amide enolate alk:ylations proved 27 markedly inferior from a number of standpoints. The use of ephedrine as a chiral auxiliary was described more than 15 years ago and, as outlined in that work, entailed the use of the carcinogenic co-solvent HMPA in the alkylation reactions. 36 In addition, difficulties in transforming the alkylated ephedrine amides into useful products were reported. We have reinvestigated the alkylation of ephedrine amides using the protocol described above for pseudoephedrine amide enolate alkylations (employing lithium chloride as an additive) and have found these alkylations to exhibit only modest diastereoselectivity.37 In addition, ephedrine amides lack the desirable process features of pseudoephedrine amides - they are typically oils. Conclusion Pseudoephedrine has been documented to be a highly practical chiral auxiliary for asymmetric alkylation reactions. The enolates of pseudoephedrine amides undergo efficient and highly diastereoselective alkylation reactions with a wide variety of alkyl halides. In addition, the low cost of the auxiliary, the crystallinity of many of the starting materials and products, and the fact that carcinogenic co-solvents are not required make the reported procedures amenable to large scale and process applications. 28 Experimental Section General Procedures. All non-aqueous reactions were performed in flame-dried round-bottomed or modified Schlenk (Kjeldahl shape) flasks, equipped with a magnetic stirring bar and fitted with a rubber septum under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula unless otherwise noted. concentrated by rotary evaporation at -25 Torr. Organic solutions were Flash column chromatography was performed as described by Still et al. 38 employing 230-400 mesh silica gel. Analytical thin-layer chromatography was performed using glass plates precoated with 0.25-mm 230400 mesh silica gel impregnated with a fluorescent indicator (254 nm). All recrystallization mixtures were cooled gradually to -20 °C prior to harvesting the product by filtration. Materials. BOMBr and BOMCl were prepared according to the literature procedure.39 Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran and ether were distilled under nitrogen from sodium benzophenone ketyl. Dichloromethane, diisopropylamine, triethylamine, chloro- trimethylsilane, acetonitrile, and toluene were distilled under nitrogen from calcium hydride. Lithium chloride was dried under vacuum at 150 °C for 24 h, then stored under a nitrogen atmosphere, or alternatively was flame-dried under vacuum immediately prior· to use. Benzyl bromide, iodomethane, isobutyl iodide, and (2-iodoethyl)benzene w~re passed through basic alumina immediately prior to use. Allyl iodide and ethyl were washed with aqueous sodium thiosulfate solution, dried over potassium carbonate, and passed through basic alumina immediately prior to use. The molarity of n-butyllithium was determined by titration against diphenylacetic acid as an indicator (average of three determinations). 40 Instrumentation. Melting points are uncorrected. Infrared data are presented as follows: frequency of absorption (cm-1), intensity of absorption (br =broad, s =strong, m 29 =medium). 1 H NMR spectra were recorded at 400 or 300 MHz, and 13 C NMR spectra were recorded at 100 or 7 5 MHz; chemical shifts are expressed in parts per million (8 scale) downfield from tetramethylsilane. 1H NMR chemical shifts are referenced to the signal for residual hydrogen in the NMR solvent (CHC13 : 8 7.26, C 6HD 5 : 8 7.15) or to tetramethylsilane. Data are presented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, m = multiplet), integration, and coupling constant in Hertz. Correlated spectroscopy (COSY) experiments were performed on aGE QE-300 MHz instrument at 23 °C using the following parameters: P2 = 7.00 )lseC, D5 = 200 msec, D8 = 10.00 )lseC, I8 = 312 )lSec, acquisition time = 159.74 msec, recycle time = 0.47 sec. Nuclear Overhauser enhancement (NOB) experiments were performed on the same instrument at 23 OC using the following parameters: P2 = 8 msec, D4 = 1 msec, D5 = 1 sec, D6 = 5 sec, L1 = 3075. 13 C NMR chemical shifts are referenced to the carbon signal for the solvent (CDC13 : 8 77.0, C 6D 6 : 8 128.0). Mass spectrometry was performed at the University of Nebraska-Lincoln, at the California Institute of Technology, or at the University of California at Irvine. Crystal structures were obtained by Dr. Joseph Ziller (University of California at Irvine). Combustion analyses were performed by Mr. Fenton Harvey (California Institute of Technology), or by Quantitative Technologies Incorporated. Chiral capillary gas chromatography (GC) analysis was carried out using an Alltech Chirasil-Val chiral fused silica capillary column, under isothermal conditions, with a column head pressure of 17 psi. Determination of Absolute Stereochemistry of Alkylation Products: The structures of alkylation products 11, 12, and 16 were determined by X-ray crystallographic analysis. Product 13 was transformed by LAB (vide infra) to the known (S)-2-methyl-1,3-propanediol benzyl ether in good yield.7b Both (R)- and (S)- Mosher ester derivatives41 of this alcohol were prepared and were identified conclusively by comparison with 1H NMR data from authentic materials).7b Products 17 and 19 form a diastereomeric pair. 30 Their hydrolysis (vide infra) produces enantiomeric acids whose configuration was established by comparison of the respective optical rotations to literature values of the known (R)-2-benzylhexanoic acid. 42 Products 12 and 18 form a diastereomeric pair; since the configuration of 12 was secured by X-ray analysis, that of 18 is detmed unambiguously. Acidic hydrolysis of product 20 produces 2-phenylbutyric acid, which was coupled with (R)-a:-methylbenzylamine as described for acid 39 (vide infra). The resulting (R)-a:-methylbenzyl amide was shown to be identical to the (R)-a:methylbenzyl amide of commercially available (S)-2-phenylbutyric acid by chiral capillary GC analysis. In every case studied, the major pseudoephedrine alkylation product results from electrophilic attack on the putative Z-enolate (R syn to the enolate oxygen) from the same face as the carbon-bound methyl group of pseudoephedrine when it is drawn in its extended conformation (Figure 1). The remaining alkylations were assumed to proceed analogously. 31 propionic anhydride H3 0 Njl_,CH3 1 OH CH3 1 CS, S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl Propionamide 1 A 1-L flask was charged with (+)-pseudoephedrine (21.0 g, 127 mmol, 1 equiv), triethylamine (21.3 mL, 153 mmol, 1.20 equiv) and dichloromethane (250 mL). The flask was placed in a water bath at 23 °C, and propionic anhydride (17.4 mL, 136 mmol, 1.07 equiv) was added to the solution in 1-mL portions over several minutes. The reaction mixture was stirred for 30 min at 23 °C, then excess anhydride was quenched by the addition of water (40 mL). The organic layer was separated and extracted with halfsaturated aqueous sodium bicarbonate solution (2 x 40 mL) and 1 N aqueous hydrochloric acid solution (2 x 40 mL). The organic extract was dried over sodium sulfate and was concentrated in vacuo to furnish a white solid. Recrystallization of the product from hot toluene (110 °C, 85 mL) furnished amide 1 as a white crystalline solid (26.9 g, 95%): mp 114-115 °C. 32 (3:1 rotarner ratio, * denotes minor rotarner peaks) 6.95-7.45 (m, 5H, ArH), 4.83 (br, 1H, OH), 4.51 (t, 1H, J = 7.2 Hz, CHOH), 4.10 (m, 2H, CHOH, NCHCH 3), 3.68* (m, 1H, NCHCH3 ), 2.77* (s, 3H, NCH 3 ), 2.40* (m, 2H, CH2 ), 2.06 (s, 3H, NCH 3), 1.73 (m, 2H, CH 2 ), 1.22* (t, 3H, J = 7.3 Hz, CH2 CH 3 ), 0.9-1.1 (m, 6H, CH 3CHN, CH2CH 3), 0.53* (d, 3H, J = 6.7 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDCIJ S: (2:1 rotarner ratio, * denotes minor rotarner peaks) 175.8, 174.8*, 142.2, 141.5*, 128.3*, 128.1, 127.9*, 127.4, 126.7*, 126.3, 76.1, 75.0*, 58.1, 57.7*, 32.1, 27.3, 26.6*, 15.2*, 14.2, 9.4*, 9.0. FTIR (neat, cm-1): 3380 (br, m, OH), 1621 (s, C=O). HRMS (FAB): Calcd for C13H 20 N02 (MHt: 222.1495 Found: 222.1490. Analysis: Calcd for C 13H 19N0 2 : C, 70.56; H, 8.65; N, 6.33 Found: C, 70.62; H, 8.36; N, 6.34. 1: 0.61 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 33 hexanoic anhydride THF, 23°C H3 0 N~CHa I 91% OH CHa 2 CS. Sl-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl Hexanamide 2 A 2-L flask was charged with (+)-pseudoephedrine (40.0 g, 242 mmol, 1 equiv) and tetrahydrofuran (500 mL). The flask was placed in a water bath at 23 °C, and hexanoic anhydride (55.5 g, 259 mmol, 1.07 equiv) was added to the solution via cannula over 10 min. The reaction mixture was stirred for 25 min at 23 °C, then the hexanoic acid was quenched by the cautious addition of saturated aqueous sodium bicarbonate solution (300 mL). Tetrahydrofuran was removed under reduced pressure, and the resulting aqueous solution was partitioned between water (500 mL) and ethyl acetate (250 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 250 mL). The combined organic extracts were dried over sodium sulfate and were concentrated to fumish a white solid. The solid was dissolved in a warm solution of ether (35 °C, 100 mL), and the solution was diluted with hot hexanes (69 °C, 100 mL). Recrystallization of the product from this 1:1 mixture of ether and hexanes afforded amide 2 as a white crystalline solid (58.2 g, 91% ): mp 62-63 °C. 34 (7:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 5H, aromatic), 4.9 (br, 1H, OH), 4.52 (d, 1H, J = 6.9 Hz, CHOH), 4.14 (m, 2H, CHOH, NCHCH 3), 3.77* (m, 1H, NCHCH 3), 2.79* (s, 3H, NCH 3), 2.42* (m, 2H, COCH2 ), 2.13 (s, 3H, NCH 3 ), 1.83 (m, 2H, COCH 2 ), 1.59 (qn, 2H, J = 7.6 Hz, COCH2CH2), CH 2CH 2CH 3 ), 0.99 (d, 1.1-1.4 3H, J (m, 4H, = 7.0 Hz, CH 3CHN), 0.86 (t, 3H, J = 7.0 Hz, CH 2CH 3), 0.59* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (75 MHz, CDC1 3) 3: (2: 1 rotamer ratio, * denotes minor rotamer peaks) . 175.2, 174.2*, 142.3, 141.6*, 128.3*, 128.0, 127.8*, 127.3, 126.7*, 126.2, 76.1, 75.1*, 58.2, 57.0*, 34.1, 33.4*, 32.4*, 31.5*, 31.3, 26.6, 24.9*, 24.5, 22.31 *, 22.29, 15.2*, 14.2, 13.82*, 13.79. FfiR (neat, cm- 1): 3378 (br, m, OH), 1618 (s, C=O). HRMS (FAB): Calcd for C 16 H26 N0 2 (MHt: 264.1965. Found: 264.1966. Analysis: Calcd for C 16H 25 N0 2 : C, 72.97; H, 9.57; N, 5.32. Found: C, 73.07; H, 9.30; N, 5.27. 2: 0.71 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 35 hydrocinnamoyl chloride THF, 0 oc 00~~ ll) OH CHa 3 (S. S)-N -(2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl Benzenepropionamide 3 A solution of hydrocinnamoyl chloride (24.4 g, 145 mmol, 1.15 equiv) in tetrahydrofuran (50 mL) was added via cannula over 10 min to an ice-cooled solution of (+)-pseudoephedrine (20.8 g, 126 mmol, 1 equiv) and triethylamine (22.8 mL, 164 mmol, 1.30 equiv) in tetrahydrofuran (300 mL). After 10 minutes, excess acid chloride was quenched by the addition of water (10 mL). The mixture was partitioned between ethyl acetate (500 mL) .and brine (40 mL), and the organic layer was separated and extracted with brine (2 x 40 mL). The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude reaction product from hot toluene ( 110 °C, 125 mL) afforded amide 3 as a white crystalline solid (31.2 g, 83%): mp 102-104 °C. 36 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, lOH, aromatic), 4.59 (br, 1H, OH), 4.48 (t, 1H, J = 7.1 Hz, CHOH), 4.20 (m, 1H, NCHCH 3), 4.01 * (dd, 1H, J = 8.4 Hz, 2.4 Hz, CHOH), 3.66* (m, 1H, NCHCH 3), 3.15* (m, 2H, CH 2Ph), 2.93 (t, 2H, J = 7.7 Hz, CH 2Ph), 2.79* (s, 3H, NCH 3), 2.49* (m, 2H, COCH2), 2.13 (m, 2H, COCH 2), 2.02 (s, 3H, NCH 3 ), 0.92 (d, 3H, J = 7.0 Hz, CH 3CHN), 0.49* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC1 3) 8: (3: 1 rotamer ratio, * denotes minor rotamer peaks) 174.3, 173.2*, 142.2, 141.5*, 141.3*, 141.1, 128.6*, 128.39, 128.36, 128.31, 128.29, 128.2*' 127.6*, 126.8*, 126.4, 126.1, 125.9*, 76.3, 75.3*, 58.2, 58.0*, 36.1, 35.4*, 32.3*, 31.5*, 31.1, 26.9, 15.2*, 14.3. FTIR (neat, cm-1): 3374 (br, m, OH), 1621 (s, C=O). HRMS (FAB): Calcd for C 19H24N0 2 (MHt: 298.1808. Found: 298.1806. Analysis: Calcd for C 19 H 23 N0 2 : C, 76.74; H, 7.80; N, 4.71. Found: C, 76.45; H, 8.00; N, 4.40. 3: 0.71 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 37 phenylacetyl chloride THF, 0 oc 88% CS. S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl Benzeneacetamide 4 An ice-cooled solution ofphenylacetyl chloride (21.1 g, 137 mmol, 1.10 equiv) in tetrahydrofuran (100 mL) was added via cannula over 15 min to a solution of (+)pseudoephedrine (20.5 g, 124 mmol, 1 equiv) and triethylamine (19.7 mL, 142 mmol, 1.14 equiv) in tetrahydrofuran (500 mL) at 0 °C. The resulting suspension was stirred for 30 min at 0 °C, then excess acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (10 mL). Volatile solvents were removed under reduced pressure, and the resulting aqueous solution was partitioned between dichloromethane (600 mL) and water (100 mL). The organic layer was separated and extracted sequentially with water (100 mL), 1 N aqueous hydrochloric acid solution (100 mL), and brine (60 mL). The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude reaction product from hot toluene (110 °C, 200 mL) afforded amide 4 as a white crystalline solid (30.9 g, 88%): mp 145-146 °C. 38 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 6.9-7.5 (m, 10H, aromatic), 4.65 (br, 1H, OH), 4.48 (t, 1H, J = 7.1 Hz, CHOH), 4.22 (m, 1H, NCHCH 3), 4.17* (m, 1H, CHOH), 3.90* (m, 1H, NCHCH 3), 3.78* (s, 2H, CH 2Ph), 3.31 (d, 2H, J = 1.3 Hz, CH 2Ph), 2.76* (s, 3H, NCH 3), 2.12 (s, 3H, NCH 3 ), 0.95 (d, 3H, J = 7.0 Hz, CH 3CHN), 0.42* (d, 3H, J = 6.7 Hz, CH 3CHN). C NMR (7 5 MHz, CDC13) o: 13 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 173.1, 172.2*, 142.2, 141.4*, 135.5*, 134.5, 128.7, 128.64, 128.58, 128.3, 128.1 *, 127.5*, 126.73*, 126.68*, 126.6*, 126.3, 76.2, 75.3*, 58.6, 41.8, 41.4*, 33.3*, 27.0, 15.0*, 14.3. FTIR (neat, cm-1): 3393 (br, m, OH), 1618 (s, C=O). HRMS (FAB): Calcd for C 18 H22 N0 2 (MHt: 284.1652. Found: 284.1646. Analysis: Calcd for C 18 H 21 N0 2 : C, 76.30; H, 7.47; N, 4.94. Found: C, 76.07; H, 7.40; N, 4.86. 4: 0.69 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 39 isovaleryl chloride THF, 0 oc 92"/o (S .S)-N-{2-Hydroxy-1-methyl-2-phenylethy])-N .3-dimethyl Butanamide 5 An ice-cooled solution of isovaleryl chloride (8.47 g, 70.3 mmol, 1.10 equiv) in tetrahydrofuran (50 mL) was added via cannula over 15 min to a solution of (+)pseudoephedrine (10.6 g, 63.9 mL, 1 equiv) and triethylamine (10.7 mL, 76.7 mmol, 1.2 equiv) in tetrahydrofuran (200 mL) at 0 °C. After 30 min, excess acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL). The mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (80 mL) and ethyl acetate (200 mL). The organic layer was separated and extracted sequentially with half saturated aqueous sodium bicarbonate solution (25 mL), two 25-mL portions of 3 N aqueous hydrochloric acid solution, and two 20-mL p01tions of brine. The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude reaction product from hot hexanes (69 °C, 25 mL) afforded amide 5 as a white crystalline solid (14.6 g, 92%): mp 73-74 °C. 40 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.20-7.45 (m, 5H, aromatic), 4.6 (m, 1H, CHOH), 4.42 (m, 1H, NCHCH 3 ), 4.01 * (m, 1H, NCHCH 3), 2.91 * (s, 3H, NCH 3), 2.81 (s, 3H, NCH 3), 2.05-2.30 (m, 3H, COCH2CH), 1.13 (d, 3H, J = 7.0 Hz, CHNCH 3 ), 0.96 (m, 6H, CH 2CH(CH 3) 2 ). (4:1 rotamer ratio, * denotes minor rotamer peaks) 174.9, 173.6*, 142.5, 141.3*, 128.7*, 128.3, 127.5, 126.9*, 126.3, 76.5, 75.5*, 58.7, 58.3*, 43.1, 42.5*, 33.2, 26.7*, 25.5, 22.8*, 22.7, 22.6, 22.4*' 22.3*' 15.3*' 14.5. FTIR (neat, cm-1): 3380 (br, s, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 15 H24 N0 2 (MHt: 250.1807. Found: 250.1816. Analysis: Calcd for C 15 H23 N0 2 : C, 72.25; H, 9.30; N, 5.62. Found: C, 72.02; H, 9.58; N, 5.43. TLC (80% EtOAc-hexanes), R; 5: 0.71 (UV, PMA). pseudoephedrine: 0.04 (UV, PMA). 41 tert-butylacetyl chloride THF, ooc 88% (S .S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.3.3-trimethyl Butanamide 6 An ice-cooled solution of tert-butylacetyl chloride (7.33 g, 54.4 mmol, 1.05 equiv) in tetrahydrofuran (50 mL) was transferred via cannula over 5 min to a solution of (+)- pseudoephedrine (8.56 g, 51.8 g, 1 equiv) and triethylamine (8.67 mL, 62.2 mL, 1.20 equiv) in tetrahydrofuran (200 mL) at 0 °C. The resulting thick white suspension was stirred at 0 OC for 65 min, then excess acid chloride was quenched by the sequential addition of saturated aqueous sodium bicarbonate solution (5 mL) and 0.5 N aqueous sodium hydroxide solution (30 mL). Tetrahydrofuran was removed under reduced pressure, and the resulting aqueous solution was extracted with dichloromethane (200 mL). The organic layer was separated and extracted sequentially with three 20-mL portions of 0.5 N aqueous sodium hydroxide solution and three 20-mL portions of 1 N aqueous hydrochloric acid solution. The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude reaction product from hot hexanes (69 °C, 40 mL) afforded amide 6 as a white crystalline solid (12.0 g, 88%): mp 68-69 °C. 42 (5: 1 rotamer ratio, * denotes minor rotamer peaks) 7.2-7.4 (m, 5H, aromatic), 4.59 (m, 1H, CHOH), 4.44 (br, m, 1H, NCHCH 3), 4.09* (m, 1H, NCHCH 3 ), 2.90* (s, 3H, NCH 3 ), 2.84 (s, 3H, NCH 3), 2.23 (d, 2H, J = 1.4 Hz, CH 2), 1.12 (d, 3H, J = 7.0 Hz, CH 3CHN), 1.06* (s, 9H, CH 2 C(CH 3) 3), 1.01 (s, 9H, CH2C(CH 3) 3). 13 C NMR (7 5 MHz, CDC13) 8: (5: 1 rotamer ratio, * denotes minor rotamer peaks) 174.4, 173.0*, 142.6, 141.2*, 128.6*, 128.3, 127.5, 126.9*, 126.3, 76.4, 75.6*, 58.7, 45.8, 45.1*, 34.1, 31.6*, 30.1*, 29.9, 15.4*, 14.5. FfiR (neat, cm-1): 3382 (br, s, OH), 1614 (s, C=O). HRMS (FAB) Calcd for C 16H 26 N0 2 (MHt: 264.1964. Found: 264.1971. Analysis: Calcd for C 16H 25 N0 2 : C, 72.97; H, 9.57; N, 5.32. Found: C, 72.73; H, 9.74; N, 5.21. TLC (80% EtOAc-hexanes), Rj- 6: 0.66 (UV, PMA). pseudoephedrine: 0.04 (UV, PMA). 43 4-phenylbutyrl chloride THF, 0 oc HaC?, ~ N~ I OH CH 3 81% 7 CS. S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl Benzenebutanamide 7 A solution of 4-phenylbutyric acid (4.57 g, 29.1 mmol, 1.20 equiv) in dichloromethane (15 mL) was charged sequentially with oxalyl chloride (2.53 mL, 29.1 mmol, 1.20 equiv) and N,N-dimethylformamide (10 J.LL, 0.13 mmol, 0.005 equiv). The latter addition resulted in vigorous bubbling, and the resulting mixture was stiiTed at 23 'C for 1 hour, during which time the bubbling ceased. The reaction mixture was cooled to 0 °C and was transferred via cannula to a solution of (+)-pseudoephedrine (4.00 g, 24.2 g, 1 equiv) and triethylamine (4.72 mL, 33.9 mmol, 1.40 equiv) in tetrahydrofuran (50 mL) at 0 °C. After 1 h, unreacted acid chloride was quenched by the addition of water (5 mL). The mixture was partitioned between ethyl acetate (400 mL) and half-saturated aqueous sodium bicarbonate solution (25 mL), and the organic layer was separated and extracted sequentially with half-saturated aqueous sodium bicarbonate solution (25 mL), two 25-mL portions of 2 N aqueous hydrochloric acid solution, and brine (25 mL). The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude reaction product from hot toluene (110 °C, 15 mL) afforded amide 7 as a white crystalline solid (6.08 g, 81 %): mp 100-102 °C. 44 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.1-7.4 (m, 10H, aromatic), 4.60 (m, 1H, CHOH), 4.53* (m, 1H, CHOH), 4.45 (m, 1H, NCHCH 3), 4.33 (br, 1H, OH), 3.90* (m, 1H, NCHCH 3), 2.92* (s, 3H, NCH 3 ), 2.75 (s, 3H, NCH 3 ), 2.642.69 (m, 2H, COCH 2 ), 2.35 (m, 2H, PhCH2 ), 2.00 (m, 2H, PhCH2CH 2), 1.10 (d, 3H, J = 6.9 Hz, CH 3CHN), 0.95* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC13) 8: (3: 1 rotamer ratio, * denotes minor rotamer peaks) 175.0, 174.0*, 142.4, 141.9*, 141.6, 141.2*, 128.6*, 126.8*, 126.4, 128.5, 128.3, 127.6, 125.9*, 76.5, 75.5*, 58.5, 58.2*, 35.4*, 35.1, 33.3, 32.8*, 26.8*, 26.3, 15.3*, 14.4. FTIR (neat, em-'): 3374 (br, m, OH), 1620 (s, C=O). HRMS (FAB): Calcd for C 20 H26 N0 2 (MHt: 312.1964. Found: 312.197 4. Analysis: Calcd for C 20H 25 N0 2 : C, 77.14; H, 8.09; N, 4.50. Found: C, 77.06; H, 7.94; N, 4.62. 7: 0.67 (UV, PMA). 4-phenylbutyric acid: 0.60 (UV). 45 ~ ~H3 ~ .. H :_ I 2-thiopheneacetyl chloride THF, 0 oc OH CH3 n ~ qH3~ ~N~S;> ;: I OH 87% CH3 8 (R .R)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl 2-Thiopheneacetamide 8 A solution of 2-thiopheneacetyl chloride (3.89 g, 24.2 mmol, 1.05 equiv) in tetrahydrofuran (10 mL, followed by a 10-mL rinse) was added via cannula to a solution of (-)-pseudoephedrine (3.81 g, 23.1 mmol, 1 equiv) and triethylamine (3.86 mL, 27.7 mmol, 1.20 equiv) in tetrahydrofuran (100 mL) at 0 °C. The resulting thick suspension was stirred for 30 min at 0 °C, then excess acid chloride was quenched by the addition of water (20 mL). Tetrahydrofuran was removed under reduced pressure, and the resulting aqueous solution was partitioned between water (20 mL) and ethyl acetate (300 mL). The organic layer was separated and extracted sequentially with 80% saturated aqueous sodium bicarbonate solution (25 mL), 2 N aqueous hydrochloric acid solution (25 mL) and brine (25 mL). The organic layer was dried over sodium sulfate and was concentrated. The crude reaction product was purified by flash column chromatography (60% ethyl acetatehexanes) affording the amide 8 as a yellow crystalline solid (5.29 g, 87%): mp 110-111 OC. 46 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 7.2-7.4 (m, 5H, aromatic), 6.9-7.0 (m, 3H, thiophene), 4.50-4.62 (m, 2H, CHOH, NCHCH 3), 3.91-4.12* (m, 2H, CHOH, NCHCH 3 ), 3.96* (s, 2H, CH 2), 3.88 (s, 2H, CH 2 ), 2.96* (s, 3H, NCH 3 ), 2.88 (s, 3H, NCH 3), 1.11 (d, 3H, J = 6.9 Hz, CH 3 CHN), 0.90* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC1 3) 3: (2: 1 rotamer ratio, * denotes minor rotamer peaks) 172.0, 171.1*, 142.1, 141.3*, 137.0*, 136.1, 128.7*, 128.4, 127.7, 126.8, 126.4, 126.1*, 126.0*, 124.7, 124.6*, 76.3, 75.5, 58.8, 58.4, 36.0, 35.5, 32.9, 27.1, 15.1, 14.2. FTIR (neat, cm-1): 3384 (br, m, OH), 1624 (s, C=O). HRMS (FAB): Calcd for C 16 H 20 N0 2S (MHY: 290.1215. Found: 290.1229. Analysis: Calcd for C 16H 19 N0 2 S: C, 66.41; H, 6.62; N, 4.84. Found:C, 66.18; H, 6.64; N, 4.64. 8: 0.59 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 47 H3 3-pyridylacetyl chloride N...H CH3 CN, THF, 15 oc I OH CH3 ~ N~N HsQ I OH CH3 97'% 9 (S, S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl3-Pyridineacetamide 9 Triethylamine (3.34 mL, 24.0 mmol, 3.00 equiv) was added to a suspension of 3pyridylacetic acid hydrochloride (2.08 g, 12.0 mmol, 1.50 equiv) in acetonitrile (60 mL). The resulting suspension was stirred at 23 OC for 10 min, then was cooled to 0 °C. Pivaloyl chloride (1.48 mL, 12.0 mmol, 1.50 equiv) was added followed by tetrahydrofuran (10 mL) to improve stirring of the thick suspension. A solution of (+)pseudoephedrine.(1.32 g, 7.99 mmol, 1 equiv) and triethylamine (1.11 mL, 7.99 mmol, 1 equiv) in tetrahydrofuran (20 mL, followed by a 3-mL rinse) was added rapidly via cannula. The mixture was warmed slowly to 15 OC over one hour, and excess anhydride was quenched by the addition of water (10 mL). Volatile solvents were removed under reduced pressure, and the resulting aqueous solution was suspended between 0.5 N aqueous sodium hydroxide solution and 10% methanol-dichloromethane (50 mL). The aqueous layer was separated and extracted with 10% methanol-dichloromethane (4 x 50 mL). The combined organic layers were washed with 1 N aqueous sodium hydroxide solution (15 mL), then were dried over sodium sulfate and were concentrated. Purification of the product by flash column chromatography, eluting with a gradient of ethyl acetatemethanol-triethylamine [(90:8:2) ---t (88:10:2)] afforded amide 9 as a white crystalline solid (2.21 g, 93%): mp 117.5-118.5 °C. 48 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 8.2-8.6 (m, 2H, two of C 5 H 4 N), 7.6-7.7 (m, 1H, one of C 5H 4 N), 7.1-7.4 (m, 6H, one of C 5H 4 N, phenyl), 4.4-4.7 (m, 2H, CHOH, NCHCH 3), 4.04.3* (m, 2H, CHOH, NCHCH 3 ), 3.80* (d, 2H, J = 1.8 Hz, CH 2 ), 3.67 (s, 2H, CH 2 ), 2.96* (s, 3H, NCH 3 ), 2.89 (s, 3H, NCH 3), 1.13 (d, 3H, J = 6.8 Hz, CH 3CHN), 0.93* (d, 3H, J = 6.8 Hz, CH 3CHN). C NMR (7 5 MHz, CDC1 3) o: 13 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 171.0, 170.8*, 149.8*, 149.6, 147.4, 147.2*, 142.1, 142.0*, 136.9*, 136.6, 131.5*, 130.6, 128.3*, 128.0, 127.7*, 127.3, 126.5*, 126.3, 123.2, 123.0*, 75.3, 74.8*, 58.4, 56.5*, 38.0, 37.4*, 31.8*, 27.1, 15.2*, 14.0. FTIR (neat, cm-1): 3385 (br, m, OH), 1626 (s, C=O). HRMS (FAB): Calcd for C 17 H 21 N2 0 2 (MHt: 285.1603. Found: 285.1596. Analysis: Calcd for C 17H 20 N 2 0 2 : C, 71.81; H, 7.09; N, 9.85. Found: C, 71.77; H, 7.08; N, 9.81. 1LC (E~N-pretreated plate, 10% MeOH-CH2Cl2), R; 9: 0.40 (UV, PMA). pseudoephedrine: 0.14 (UV, PMA). 49 H3 3-pyridylacetyl chloride N'H CH3CN, THF, 15 oc I OH CH3 H3Q ~ N~N I OH CH3 9 (S .S)-N-{2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl 3-Pyridineacetamide 9 Amide 9 could also be purified by recrystallization. Following a procedure similar to that described above, using (+)-pseudoephedrine (1.49 g, 8.99 mmol, 1 equiv), triethylamine (3.38 mL, 24.3 mmol, 3.00 equiv), 3-pyridylacetic acid hydrochloride (2. 11 g, 12.1 mmol, 1.35 equiv), and pivaloyl chloride (1.50 mL, 12.1 mmol, 1.35 equiv), the crude reaction product was recrystallized from hot toluene (110 °C, 8 mL) furnishing the amide 9 as a crystalline solid (1.83 g, 72%). Spectroscopic data were identical to those listed above: mp 117.5-118.5 °C. Analysis: Calcd for C 17 H 20 N 2 0 2 : C, 71.81; H, 7.09; N, 9.85. Found: C, 71.60; H, 7.18; N, 9.73. 50 rrBuLi, LiCI; methyl glycolate H3 0 II N~ THF, 23 oc OH I OH CH3 10 (S,S)-(x-Hydroxy-N -{2-hydroxy-1-methyl-2-phenylethyl)-N-methyl Acetamide 1 0 A solution of n-butyllithium in hexanes (2.37 M, 5.62 mL, 13.3 mmol, 0.5 equiv) was added to an ice-cooled suspension of lithium chloride (3.39 g, 79.9 mmol, 3.00 equiv) and (+)-pseudoephedrine (4.40 g, 26.6 mmol, 1 equiv) in tetrahydrofuran (200 mL), and the suspension was stirred at 0 OC for 30 min. Methyl glycolate (4.11 mL, 53.3 mmol, 2.00 equiv) was added via syringe over 5 min, and the mixture was warmed to 23 OC and stirred at that temperature for 3 h. A solution of 0.5 N aqueous sodium hydroxide (100 mL) was added, and the biphasic mixture was stirred at 23 °C for 1 h. Volatile organic solvents were removed under reduced pressure, and the resulting aqueous solution was extracted with five 50-mL portions of 10% methanol-dichloromethane. The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the product by flash column chromatography eluting with a gradient of methanoldichloromethane (6 ~ 10%) afforded amide 10 as a colorless oil which slowly solidified (5.55 g, 93%): mp 61-63 °C. 51 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 7.20-7.45 (m, 5H, aromatic), 4.60 (m, 2H, CH2 0H), 4.36* (m, 2H, CH 20H), 4.10-4.20 (m, 2H, CHOH, NCHCH 3 ), 3.75* (br, lH, OH), 3.65 (br, lH, OH), 3.55-3.65* (m, 2H, CHOH, NCHCH 3), 3.20 (br, lH, OH), 3.01 * (s, 3H, NCH 3 ), 2.75 (s, 3H, NCH 3 ), 2.40* (br, lH, OH), 1.08 (d, 3H, J = 6.6 Hz, CH 3 CHN), 0.99* (d, 3H, J = 6.8 Hz, CH 3CHN). (2: 1 rotamer ratio, * denotes minor rotamer peaks) 172.9, 172.6*, 141.6, 141.1 *, 128.7*, 128.4, 127.9*, 126.7, 126.5, 75.6, 74.9*, 60.1, 60.0*, 57.3*, 56.7, 29.0, 27.1*, 15.0*, 14.0. FTIR (neat, cm-1): 3390 (br, s, OH), 1634 (s, C=O). HRMS (EI): Calcd for C 12H 18 N0 3 (MHt: 224.1287. Found: 224.1289. Analysis: Calcd for C 12 H 17 N0 3 : C, 64.55; H, 7.67; N, 6.27. Found: C, 64.53; H, 7.58; N, 6.20. TLC (E~N-pretreated plate, 10% Me0H-CH2Cl2), Rf 10: 0.44 (UV, PMA). pseudoephedrine: 0.11 (UV, PMA). 52 LOA, LiCI; C6 H 5 CH2Br THF, 0 oc Oy!~~CHa 00"/o f1SCRl.2Sl-N-C2-Hydroxy-1-methyl-2-phenylethyl)-N.2-dimethyl 0 H CH3 CH2CsHs 11 Benzenepropionamide ll A 3-necked, 2-L flask equipped with a mechanical stirrer was charged with lithium chloride (25.0 g, 596 mmol, 6.00 equiv), diisopropylamine (31.3 mL, 224 mmol, 2.25 equiv) and tetrahydrofuran (120 mL). The resulting suspension was cooled to -78 OC and a solution of n-butyllithium in hexanes (2.43 M, 85.1 mL, 207 mmol, 2.08 equiv) was added via cannula. The suspension was warmed briefly to 0 °C, then was cooled to -78 0 C. An ice-cooled solution of amide 1 (22.0 g, 99.4 mmol, 1 equiv) in tetrahydrofuran (300 mL) was added to the reaction flask via cannula. The reaction mixture was stirred at - 78 OC for 1 h, at~ C for 15 min, at 23 ° C for 5 min, and finally was cooled to 0 °C, whereupon benzyl bromide (17.7 mL, 149 mmol, 1.50 equiv) was added. The mixture was stirred at 0 OC for 15 min then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was partitioned between saturated aqueous ammonium chloride solution (800 mL) and ethyl acetate (500 mL), and the aqueous layer was separated and extracted with two 150-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and were concentrated to afford a yellow solid. Recrystallization of the product from hot toluene (110 °C, 100 mL) afforded amide 11 as a white crystalline solid (27.8 g, 90% ): mp 136-137 °C. Amide 11 (30 mg, 0.096 mmol, 1 equiv) was silylated with chlorotrimethylsilane (34 J..t.L, 0.27 mmol, 2.8 equiv) and triethylamine (49 J..t.L, 0.35 mmol, 3.6 equiv) in dichloromethane (1 mL) at 23 OC for 10 min, and chiral capillary GC analysis43 of the resulting trimethylsilyl ether established that amide 11 was of ~99% de. 53 (3:1 rotamer ratio, * denotes minor rotamer peaks) 6.9-7.4 (m, 10H, aromatic), 4.45 (m, 1H, CHOH), 4.25 (br, 1H, OH), 3.96* (m, 1H, CHOH), 3.80* (m, 1H, NCHCH 3 ), 3.36* (dd, 1H, 11 = 13.1 Hz, 12 = 6.92 Hz, CHPh), 3.01 (m, 1H, NCHCH 3), 2.75* (m, 1H, COCH), 2.70* (s, 3H, NCH 3 ), 2.45-2.59 (m, 3H, COCH, CH 2 Ph), 2.08 (s, 3H, NCH 3 ), 1.05* (d, 3H, J = 7.0 Hz, COCHCH 3), 1.02 (d, 3H, J = 6.5 Hz, CH 3CHN), 0.83 (d, 3H, J = 7.0 Hz, COCHCH 3), 0.59* (d, 3H, J = 6.8 Hz, CH 3CHN). (3: 1 rotamer ratio, * denotes minor rotamer peaks) 178.2, 177.2*, 142.3, 141.1 *, 140.5*, 139.9, 129.2*, 128.9, 128.6*, 128.31 *, 128.26, 127.5*, 126.8*, 126.4, 126.2, 76.4, 75.2*, 58.0, 40.3, 40.0*, 38.9, 38.1*, 32.3, 27.1*, 17.7*, 17.4, 15.5*' 14.3. FTIR (neat, cm-1): 3384 (br, m, OH), 1617 (s, C=O). HRMS (FAB): Calcd for C20H26 N0 2 (MHt: 312.1965. Found: 312.1972. Analysis: Calcd for C20 H25 N0 2 : C, 77.14; H, 8.09; N, 4.50. Found: C, 76.87; H, 8.06; N, 4.50. TLC (80% EtOAc-hexanes), R; 11: 0.46 (UV, PMA). 1: 0.24 (UV, PMA). benzyl bromide: 0.70 (UV, PMA). 54 LOA, LiCI; n-Bul THF, 0 oc 00"/o Oyr~~CHa 0 H CH3 CH2(CH2)2CH3 12 fOSCRl.2SJ-N-C2-Hydroxy-1-methyl-2-phenylethy])-N.2-dimethyl Hexanamide 12 A 3-necked, 2-L flask equipped with a mechanical stirrer was charged with lithium chloride (16.8 g, 396 mmol, 6.00 equiv), diisopropylamine (20.8 mL, 149 mmol, 2.25 equiv), and tetrahydrofuran (175 mL). The resulting suspension was cooled to -78 °C, and a solution of n-butyllithium in hexanes (1.73 M, 79.4 mL, 137.4 mmol, 2.08 equiv) was added via cannula. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (14.6 g, 66.1 mmol, 1 equiv) in tetrahydrofuran (150 mL) was added to the reaction flask by cannula, and the reaction was stirred at -78 °C for 1 h, at 0 °C for 15 min, at 23 °C for 5 min, and finally was cooled to 0 °C, whereupon 1-iodobutane (22.6 mL, 198 mmol, 3.00 equiv) was added. The mixture was stirred at 0 OC for 1.5 h then was quenched by the addition of saturated aqueous ammonium chloride solution ( 10 mL). The mixture was pattitioned between saturated aqueous ammonium chloride solution (800 mL) and ethyl acetate (500 mL). The aqueous layer was separated and extracted with two 150-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and were concentrated. Recrystallization of the product from hot hexanes (69 °C, 100 mL) afforded amide 12 as a white crystalline solid (14.8 g, 80%): mp 65.5-66.5 °C. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 12 was of ~99% de. 55 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.00--7.45 (m, 5H, aromatic), 5.17 (br, 1H, OH), 4.55 (t, 1H, J = 7.2 Hz, CHOH), 4.06 (m, 1H, NCHCH 3), 3.90* (m, 1H, NCHCH 3), 2.77 (s, 3H, NCH 3 ), 2.70* (m, 1H, COCHCH 3), 2.22 (s, 3H, NCH 3 ), 2.17 (m, 1H, COCHCH 3 ), 1.70 (m, 2H, COCHCH 2), 1.40* (m, 2H, COCHCH2), 1.02 (d, 3H, J = 7.2 Hz, CH 3CHN), 0.99 (d, 3H, J = 6.8 Hz, COCHCH 3), 0.90-1.25 (m, 4H, CH 3CH 2CH 2), 0.85 (t, 3H, J = 7.0 Hz, CH 2CH 3), 0.62* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC13) 3: (5:1 rotamer ratio, * denotes minor peaks) 179.2, 177.8*, 142.6, 141.2*, 128.6*, 128.3*, 128.2, 127.4, 126.8*, 126.2, 76.4, 75.4*, 59.1, 57.8*, 36.5, 35.8*, 33.7, 33.4, 29.7*, 29.5, 27.0*, 22.9*, 22.7, 18.0*, 17.3, 15.3*, 14.~. 14.1*, 14.0. FTIR (neat, cm-1): 3382 (br, m, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 17 H28 N0 2 (MHt: 278.2121. Found: 278.2124. Analysis: Calcd for C 17H 27 N0 2 : C, 73.61; H, 9.81; N, 5.05. Found: C, 73.40; H, 9.71; N, 5.11. 1LC (80% EtOAc-hexanes), R; 12: 0.61 (UV, PMA). 1: 0.24 (UV, PMA). 56 H3 0 LOA, LiCI; BOM-Br I THF, -78 oc N~CH 3 OH CHa 1 80% r1SCR).2SJ-N-(2-Hydroxy-1-methyl-2-phenylethyn-N. 2-dimethyl-3-benzyloxy Propionamide 1 3 A solution of n-butyllithium in hexanes (2.37 M, 1.53 mL, 3.62 mmol, 2.08 equiv) was added to a suspension of lithium chloride (516 mg, 12.2 mmol, 7.00 equiv) and diisopropylamine (0.549 mL, 3.92 mmol, 2.25 equiv) in tetrahydrofuran (7 mL) at-78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (385 mg, 1.74 mmol, 1 equiv) in tetrahydrofuran (6 mL, followed by a 1-mL rinse) was added via cannula. The mixture was stilTed at -78 OC for 1 h, at 0 OC for 15 min, at 23 °C for 5 min, and finally was cooled to -78 °C, whereupon benzyloxymethyl bromide (0.378 mL, 2.96 mmol, 1.70 equiv) was added. The reaction mixture was stirred at -78 OC for 1 h 25 min, then was quenched at -78 OC by the addition of methanol (0.6 mL). The mixture was warmed to 23 OC and pa.Ititioned between saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (30 mL). The aqueous layer was separated and extracted with two 30-mL portions of ethyl acetate. The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the product by flash column chromatography (55% ethyl acetate-hexanes) afforded amide 13 as a colorless oil which slowly solidified (477 mg, 80%): mp 65-66 °C. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 13 was of 98% de. 57 (3:2 rotamer ratio, * denotes minor rotamer peaks) 7.0--7.4 (m, 10H, aromatic), 4.54 (m, 1H, CHOH), 4.18-4.4.4 (m, 3H, NCHCH 3 , PhCH20), 4.03* (m, 1H, NCHCH 3 ), 3.70 (m, 2H, PhCH2 0CH 2), 3.25* (m, 2H, PhCH 20CH 2), 3.02* (m, 1H, COCHCH3 ), 2.84 (s, 3H, NCH 3 ), 2.72 (m, 1H, COCHCH 3), 2.31 (s, 3H, NCH 3 ), 0.98* (d, 3H, J = 6.6 Hz, COCHCH3), 0.97 (d, 3H, J = 6.6 Hz, CH 3CHN), 0.96 (d, 3H, J = 6.8 Hz, COCHCH 3), 0.59* (d, 3H, J = 6.7 Hz, CH 3CHN). C NMR (7 5 MHz, CDC1 3) o: 13 (1:1 rotamer ratio) 177.0, 175.5, 142.3, 141.8, 138.2, 137.1, 128.4, 128.3, 128.2, 128.0, 127 .5, 126.9, 126.4, 76.3, 75.4, 73.9, 73.5, 73.3, 73.0, 58.4, 37.4, 35.8, 33.0, 27.0, 15.8, 14.7, 14.4, 14.2. FTIR (neat, cm-1): 3386 (br, m, OH), 1618 (s, C=O). HRMS (FAB): Calcd for C 21 H 27 N0 3 (Mt: 341.1991. Found: 341.2006. Analysis: Calcd for C21 H 27 N0 3 : C, 73.87; H, 7.97; N, 4.10. Found: C, 73.99; H, 8.15; N, 4.02. TLC (80% EtOAc-hexanes), R; 13: 0.44 (UV, PMA). 1: 0.31 (UV, PMA). 58 LOA, LiCI; C 6 H 5 C~CH 2 1 THF, 0 oc 86% [ 1S (R) .2S)J-N -(2-Hydroxy-1-methyl-2-phenylethyl)-N .2-dimethyl Benzenebutanamide ti A solution of n-butyllithium in hexanes (2.37 M, 10.7 mL, 25.4 mmol, 2.08 equiv) was added dropwise to a suspension of lithium chloride (3.10 g, 73.2 mmol, 6.00 equiv) and diisopropylamine (3.90 mL, 27.8 mmol, 2.28 equiv) in tetrahydrofuran (50 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An icecooled solution of amide 1 (2.70 g, 12.2 mmol, 1 equiv) in tetrahydrofuran (40 mL, followed by a 2-mL rinse) was added via cannula over 4 min. The mixture was stirred at -78 °C for 1 h, at 0 °C for 10 min, at 23 OC for 3 minutes, and finally was cooled to 0 °C, whereupon (2-iodoethyl)benzene (4.42 mL, 30.5 mmol, 2.50 equiv) was added. The reaction mixture was stirred at 0 OC for 1.5 h, then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). TI1e mixture was partitioned between half-saturated brine (200 mL) and ethyl acetate (30 mL). The aqueous layer was separated and extracted with two 75-mL portions of ethyl acetate. The combined organic fractions were washed with two 5-mL portions of brine, then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (15 ~ 52%) afforded amide 14 as a colorless oil (3.43 g, 86% ). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 14 was of 95% de. 59 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10 H, aromatic), 4.63 (d, 1H, J = 7.6 Hz, CHOH), 4.54* (d, 1H, J = 8.7 Hz, CHOH), 4.42 (br, m, 1H, CHNCH 3), 3.99* (m, 1H, CHNCH 3), 2.93* (s, 3H, NCH 3), 2.72 (s, 3H, NCH 3), 2.40-2.65 (m, 3H, PhCH 2 CH 2 CH), 2.18* (m, 1H, one of PhCH 2 CH 2 ), 1.99 (m, 1H, one of PhCH 2CH 2), 1.73* (m, 1H, one of PhCH2 CH 2), 1.62 (m, 1H, one of PhCH 2CH 2), 1.15 (d, 3H, J = 7.0 Hz, CH 3CHCH 2 ), 1.10 (d, 3H, J = 6.8 Hz, CH 3CHN), 0.99* (d, 3H, J = 6.9 Hz, CH 3CHN). (3: 1 rotamer ratio, * denotes minor rotamer peaks) 178.4, 177.1 *, 142.6, 141.8, 141.4*, 128.6*, 128.4, 128.3, 127 .5, 126.9*' 126.3, 125.8, 76.3, 75.4*, 58.8, 57.8*, 35.6, 35.3, 35.2*, 33.4, 32.9, 27.0*, 17.9*, 17.3, 17.2*, 15.4. FTIR (neat, cm-1): 3381 (br, s, OH), 1621 (s, C=O). HRMS (FAB): Calcd for C 21 H28 N0 2 (MHt: 326.2120. Found: 326.2099. 1LC (80% EtOAc-hexanes), R; 14: 0.49 (UV, PMA). 1: 0.27 (UV, PMA). 60 LOA, liCI; BrCH 2 C02 t-Bu THF, -78 oc 78"/o [ 1SCR) .2S)-N-C2-Hydroxy-1-methyl-2-phenylethyl)-N.2-dimethyl tert- Butyloxycarbonylpropionamide 1 5 A solution of n-butyllithium in hexanes (2.37 M, 10.7 mL, 25.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (3.10 g, 73.2 mmol, 6.00 equiv) and diisopropylamine (3.90 mL, 27.8 mmol, 2.28 equiv) in tetrahydrofuran (50 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (2.70 g, 12.2 mmol, 1 equiv) in tetrahydrofuran (40 mL, followed by a 2-mL rinse) was added via cannula. The resulting mixture was stirred at -78 OC for 30 min, at 0 °C for 10 min, at 23 OC for 3 min, and finally was cooled to -78 OC whereupon tert-butyl bromoacetate (3.60 mL, 24.4 mmol, 2.00 equiv) was added. The reaction mixture was stirred at -78 OC for 3.9 h, then was quenched at -78 OC by the addition of methanol (2 mL). The mixture was warmed to 0 °C, then was quenched further with saturated aqueous ammonium chloride solution (15 mL). The mixture was warmed to 23 °C, then was partitioned between half-saturated brine (200 mL) and ethyl acetate (30 mL), and the aqueous layer was separated. The aqueous layer was extracted with two 75-mL portions of ethyl acetate. The combined organic extracts were washed with brine (2 x 15 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (30 ~ 53%) afforded amide 15 as a colorless oil (3.20 g, 78%). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 15 was of 96% de. 61 1 H NMR (300 MHz, CDC13) 8: (1:1 rotamer mixture) 7.20-7.45 (m, 5H, aromatic), 4.73 (m, 1H, CHOH), 4.59 (m, 1H, CHOH), 4.20 (m, 2H, CHNCH 3), 2.98 (s, 3H, NCH 3), 2.93 (s, 3H, NCH 3 ), 2.74 (dd, 1H, 1 1 = 16.7 Hz, 12 = 9.1 Hz, one of CH 2 ), 2.30 (m, 1H, one of CH 2 ), 1.43 (s, 9H, C(CH 3) 3), 1.10 (d, 3H, J = 7.0 Hz, CH 3), 0.97 (d, 3H, J = 6.8 Hz, CH 3 ). 13 C NMR (7 5 MHz, CDC13) 8: (1:1 rotamer mixture) 177.3, 176.3, 173.3, 172.0, 142.3, 141.6, 128.5, 128.3, 128.0, 127.6, 127.1, 126.6, 80.5, 76.2, 75.8, 59.5, 58.7' 39.8, 39.5, 33.3, 32.0, 28.1, 27.0, 17.5, 16.9, 15.9, 14.3. FTIR (neat, cm-1): 3417 (br, m, OH), 1731 (s, C=O), 1622 (s, C=O). HRMS (FAB): Calcd for C 19H 30 N0 4 (MHt: 336.2175. Found: 336.217 6. TLC (80% EtOAc-hexanes), R; 15: 0.56 (UV, PMA). 1: 0.29 (UV, PMA). tert-butylbromoacetate: 0.17 (PMA). 62 Oyr:~ OH CHa ll.) 3 LOA, LiCI; CH 3 1 THF, 0 oc 99% [IS (S).2Sl-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N .2-dimethyl Benzenepropionamide 16 A solution of n-butyllithium in hexanes (1.39 M, 7.48 mL, 10.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (2.12 g, 50.0 mmol, 10.0 equiv) and diisopropylamine (1.55 mL, 11.1 mmol, 2.21 equiv) in tetrahydrofuran (18 mL) at -78 OC. The resulting suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of amide 3 (1.49 g, 5.00 mmol, 1 equiv) in tetrahydrofuran (20 mL) was added dropwise via cannula. The reaction mixture was stirred at-78 OC for 1.3 h, at 0 OC for 15 min, at 23 °C for 5 min, and finally was cooled to 0 °C, whereupon iodomethane (1.24 mL, 20.0 mmol, 4.00 equiv) was added. The reaction mixture was stin·ed at 0 OC for 55 min, then was quenched by the addition of saturated aqueous ammonium chlmide solution (10 mL). The mixture was partitioned between saturated aqueous ammonium chloride solution (150 mL) and ethyl acetate (100 mL), and the layers were separated. The aqueous layer was extracted with two 50-mL portions of ethyl acetate, and the combined organic extracts were dried over sodium sulfate and were concentrated. Pmification of the residue by flash chromatography (55% ethyl acetate-hexanes) afforded amide 16 as an oil which slowly solidified (1.54 g, 99%): mp 79-81 °C. Chiral capillary GC analysis 43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 16 was of 94% de. 63 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 6.95-7.4 (m, lOH, aromatic), 5.25 (br, 1H, OH), 4.51 (t, 1H, J = 7.0 Hz, CHOH), 3.97* (m, 1H, CHOH), 3.75 (m, 1H, NCHCH 3), 3.15* (m, 1H, NCHCH 3), 3.06 (m, 1H, COCHCH 3), 2.71* (s, 3H, NCH 3), 2.58* (m, 2H, CH 2Ph), 2.45 (m, 2H, CH 2 Ph), 1.93 (s, 3H, NCH 3), 1.34* (d, 3H, J = 6.3 Hz, COCHCH 3), 1.00 (d, 3H, J =7.0 Hz, CH 3CHN), 0.93 (d, 3H, J = 6.4 Hz, COCHCH 3), 0.30* (d, 3H, J =6.8 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC1 3) 0: (3: 1 rotamer ratio, * denotes minor rotamer peaks) 178.1, 177.0*, 142.3, 141.3*, 140.2*, 139.9, 128.94, 128.86*, 128.6*, 128.34, 128.29*, 128.2, 127.4, 126.7*, 126.3, 126.2, 126.1 *, 76.1, 75.4*, 60.3, 58.1*, 41.2*, 40.3, 39.0, 38.2*, 33.9, 27.0*, 18.2*, 17.6, 14.8*, 14.2. FTIR (neat, cm-1): 3374 (br, m, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 20H26 N0 2 (MHt: 312.1965. Found: 312.1965. Analysis: Calcd for C20H25 N0 2 : C, 77.14; H, 8.09; N, 4.50. Found: C, 76.86; H, 8.31; N, 4.41. TLC (80% EtOAc-hexanes), R; 16: 0.53 (UV, PMA). 3: 0.45 (UV, PMA). 64 o;:~ OH CH3 3 v LOA, LiCI; CH3I THF, -78 oc 95% [ 1S(S).2Sl-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N .2-dimethyl Benzenepropionamide A solution of n-butyllithium in hexanes (2.37 M, 7.38 mL, 17.5 mmol, 2.08 equiv) was added to a suspension of lithium chloride (2.14 g, 50.4 mmol, 6.00 equiv) and diisopropylamine (2.65 mL, 18.9 mmol, 2.25 equiv) in tetrahydrofuran (25 mL) at -78 °C. The resulting suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of amide 3 (2.50 g, 8.41 mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 3-mL rinse) was added dropwise via cannula. The reaction mixture was stilTed at -78 'C for 1 h, at 0 OC for 15 min, at 23 OC for 5 min, and finally was cooled to -78 °C, whereupon iodomethane (2.00 mL, 32.1 mmol, 3.80 equiv) was added. The reaction mixture was stirred at -78 OC for 8 h then was quenched at -78 OC by the addition of methanol (1.65 mL). The mixture was warmed to 23 OC and was treated with halfsaturated aqueous ammonium chloride solution (10 mL). Volatile solvents were removed under reduced pressure, and the resulting aqueous solution was partitioned between saturated aqueous ammonium chloride solution (200 mL) and ethyl acetate (40 mL). The aqueous layer was separated and extracted with two 40-mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the product by flash chromatography (50% ethyl acetate-hexanes) afforded amide 16 as a white crystalline solid (2.49 g, 95%). Spectroscopic data were identical to those listed above. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 16 was of 97% de. 65 00~~ OH CHa v 3 LDA, UCI;n-Bul THF, 0 oc ~ 9H30 ~t;J~CH2Ph OH CH3 CH2(CH2)2CHa 90% 17 f1SCS).2SJ-a-Butyl-N -(2-hydroxy-1-methyl-2-phenylethyl)-N -methyl Benzene- propionamide 1 7 A solution of n-butyllithium in hexanes (2.37 M, 17.0 mL, 40.3 mmol, 2.08 equiv) was added to a suspension of lithium chloride (4.94 g, 117 mmol, 6.00 equiv) and diisopropylamine (6.12 mL, 43.7 mmol, 2.25 equiv) in tetrahydrofuran (40 mL) at-78 °C. The resulting suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of amide 3 (5.50 g, 19.4 mmol, 1 equiv) in tetrahydrofuran (35 mL, followed by a 5-mL rinse) was added dropwise via cannula. The reaction mixture was stitTed at -78 CC for 50 min, at 0 OC for 13 min, at 23 OC for 4 min, and finally was cooled to 0 °C, whereupon 1-iodobutane (5.52 mL, 48.5 mmol, 2.50 equiv) was added. The mixture was stirred at 0° C for 1 h, then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was partitioned between saturated aqueous ammonium chloride solution (400 mL) and ethyl acetate (150 mL). The aqueous layer was separated and extracted with two 150-mL portions of ethyl acetate. The combined organic fractions were washed with brine (25 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (45 -7 60%) afforded amide 17 as a yellow oil (6.14 g, 90% ). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 17 was of 98% de. 66 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10H, aromatic), 5.2 (br, 1H, OH), 4.49 (t, 1H, J = 6.9 Hz, CHOH), 4.02* (m, 1H, CHOH), 3.90 (m, 1H, NCHCH 3 ), 3.78* (m, 1H, NCHCH 3), 3.03 (m, 1H, COCH), 2.70* (s, 3H, NCH 3), 2.57 (m, 2H, CH 2Ph), 2.02 (s, 3H, NCH 3 ), 0.93-1.9 (m, 6H, CH 3CH 2CH 2 CH 2 ), 0.92 (d, 3H, J = 7.0 Hz, CH 3CHN), 0.84 (t, 3H, J = 7.2 Hz, CH 3CH 2 ), 0.16* (d, 3H, J = 6.7 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC13) 8: (4:1 rotamer ratio, * denotes minor rotamer peaks) 177.7, 176.7*, 142.2, 141.1 *, 140.2*, 139.8, 128.9, 128.6*, 128.4, 128.3*, 128.24*, 128.16, 127.4, 126.8*, 126.32, 126.29, 126.1 *, 75.8, 75.3*, 60.0, 58.2*, 44.9, 44.2*, 39.8*, 39.5, 33.6, 33.1, 29.9*, 29.5, 27.0*, 22.9*, 22.8, 14.4*' 14.3, 14.0*' 13.9. FTIR (neat, cm-1): 3404 (s, br, OH), 1624 (m, C=O). HRMS (FAB): Calcd for C 23H 29NO (M-H 20t: 335.2251. Found: 335.2234. 1LC (60% EtOAc-hexanes), R; 17: 0.42 (UV, PMA). 3: 0.28 (UV, PMA). 67 ~ ~H 3 ~ LOA, LiCI; Mel OH CH3 THF, 0 oc ~N~CH3 2 ~% H3 0 N~CH3 I ;: OH CH 3 Me 18 £1S(S).2S)-N -(2-hydroxy-1-methyl-2-phenylethy])-N.2-dimethy1 Hexanamide 1 8 A solution of n-butyllithium in hexanes (1.39 M, 7.48 mL, 10.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (2.12 g, 50.0 mmol, 10.0 equiv) and diisopropylamine (1.55 mL, 11.1 mmol, 2.21 equiv) in tetrahydrofuran (18 mL) at-78 °C. The resulting suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of amide 2 (1.32 g, 5.00 mmol, 1 equiv) in tetrahydrofuran (15 mL, followed by a 5-mL rinse) was added dropwise to the reaction flask via cannula. The reaction mixture was stirred at -78 OC for 50 min, at 0 OC for 15 min, at 23 OC for 5 min, and fmally was cooled to 0 °C, whereupon iodomethane (1.24 mL, 20.0 mmol, 4.00 equiv) was added. The mixture was stirred at 0 °C for 55 min, then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The reaction mixture was partitioned between saturated aqueous ammonium chloride solution (150 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted with two 50-mL pmtions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate-hexanes) furnished amide 18 as a yellow oil (1.30 g, 94%). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 18 was of 94% de. 68 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 5H, aromatic), 5.30 (br, 1H, OH), 4.56 (t, 1H, J = 6.8 Hz, CHOH), 4.16* (d, 1H, J = 8.6 Hz, CHOH), 3.95 (m, 1H, NCHCH 3), 2.82* (s, 3H, NCH 3), 2.70 (m, 1H, COCHCH 3), 2.18 (s, 3H, NCH 3 ), 2.15* (m, lH, COCHCH3 ), 1.78 (m, 2H, COCHCH 2), 1.0-1.4 (m, 4H, CH 3CH 2CH 2), 1.33* (d, 3H, J = 6.7 Hz, COCHCH 3), 1.08 (d, 3H, J = 7.0 Hz, CH 3CHN), 0.92 (d, 3H, J = 6.8 Hz, COCHCH 3), 0.87 (t, 3H, J = 6.9 Hz, CH 3CH 2), 0.69* (d, 3H, J = 6.7 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC1 3) 8: (3:1 rotamer ratio, * denotes minor rotamer ratio) 178.9, 177.9*, 142.5, 141.5*, 128.5*, 128.0, 127.3, 126.8*, 126.1, 76.3, 75.2*, 59.8, 57.9*, 36.4, 35.5*, 34.2*, 33.9, 33.6, 29.5, 27.0*, 22.7, 17.6*. 17.3, 15.5*, 14.3, 13.9. FTIR (neat, cm-1): 3382 (br, m, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 17 H28 N0 2 (MHt: 278.2121. Found: 278.2119. TLC (80% EtOAc-hexanes), R; 18: 0.56 (UV, PMA). 2: 0.37 (UV, PMA). 69 Hs 0 N~CH3 I OH CH 3 2 H3 0 LOA, LiCI; Mel THF, -78 oc N~CHs I OH 00% .:: CH 3 Me 18 USCSl.2Sl-N-C2-hydroxy-1-methyl-2-phenylethy])-N.2-dimethyl Hexanamide 18 A 3-necked, 1-L flask equipped with a mechanical stiiTer was charged with lithium chloride (7.73 g, 182 mmol, 6.00 equiv), diisopropylamine (9.58 mL, 68.3 mmol, 2.25 equiv), and tetrahydrofuran (75 mL). The resulting suspension was cooled to -78 °C, and a solution of n-butyllithium in hexanes (1.71 M, 36.9 mL, 63.2 mmol, 2.08 equiv) was added via cannula. The suspension was wa1med briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 2 (8.00 g, 30.4 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added to the reaction flask via cannula. The reaction mixture was stin·ed at -78 °C for 1 h, at 0 OC for 15 min, at 23 OC for 5 min, and finally was cooled to -78 °C, whereupon iodomethane (5.67 mL, 91.1 mmol, 3.00 equiv) was added. The mixture was stirred at -78 OC for 6 h, then was quenched by the addition of methanol (7.0 mL). The mixture was warmed to 23 °C and was treated with saturated aqueous ammonium chloride solution (10 mL). Volatile organic solvents were removed by rotary evaporation, and the resulting aqueous solution was partitioned between saturated aqueous ammonium chloride solution (400 mL) and ethyl acetate (130 mL). The aqueous layer was separated and extracted with two 130-mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and were concentrated. Pmification of the residue by flash chromatography (50% ethyl acetate-hexanes) afforded amide 18 as a yellow oil (7.49 g, 89% ). Spectroscopic data were identical to those listed above. 43 Chiral capillary GC analysis of the corresponding trimethylsilyl ether, prepared as desc1ibed above for amide 11, established that amide 18 was of 96% de. 70 H3 0 N~CH3 I OH CH3 2 87"/o £1S<Rl.2SJ-o.-Butyl-N-(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl 19 Benzene- propionamide 1 9 A 3-necked, 2-L flask equipped with a mechanical stirrer was charged with lithium chloride (19.3 g, 456 mmol, 6.00 equiv), diisopropylamine (23.9 mL, 170.8 mmol, 2.25 equiv), and tetrahydrofuran (200 mL). The resulting suspension was cooled to -78 °C, and a solution of n-butyllithium in hexanes (2.43 M, 65.0 mL, 158 mmol, 2.08 equiv) was added via cannula. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 2 (20.0 g, 75.9 mmol, 1 equiv) in tetrahydrofuran (150 mL) was added to the reaction flask via cannula. The reaction mixture was stirred at -78 °C for 50 min, atO °C for 15 min, at 23 OC for 5 min, and finally was cooled to 0 °C, whereupon benzyl bromide (13.6 mL, 113.9 mmol, 1.50 equiv) was added. The mixture was stirred at 0 OC for 40 min, then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). Volatile organic solvents were removed by rotary evaporation, and the resulting aqueous solution was partitioned between saturated aqueous ammonium chloride solution (700 mL) and ethyl acetate (150 mL). The aqueous layer was separated and extracted with three 150-mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and were concentrated. Recrystallization of the crude product from hot toluene (110 °C, 100 mL) afforded amide 19 as white crystals (23.3 g, 87%): mp 120-121 °C. Chiral capillary GC analysis 43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 19 was of ~99% de. 71 (6:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.45 (m, 10H, aromatic), 4.36 (m, 1H, CHOH), 4.15 (br, 1H, OH), 3.98* (m, 1H, CHOH), 3.35* (m, 1H, NCHCH 3 ), 2.99 (m, 1H, NCHCH 3), 2.72* (s, 3H, NCH 3), 2.53-2.67 (m, 3H, COCH, COCHCH 2 Ph), 2.12 (s, 3H, NCH 3), 1.9 (m, 2H, PhCH 2CHCH 2 ), 1.1-1.4 (m, 4H, CH 3CH 2CH 2), 0.87 (t, 3H, J = 7.0 Hz, CH 3CH 2), 0.77 (m, 3H, CH 3CHN), 0.64* (d, 3H, J = 6.2 Hz, CH 3CHN). 13 C NMR (7 5 MHz, CDC1 3) 8: (4:1 rotamer ratio, * denotes minor rotamer peaks) 177.9, 176.6*, 142.2, 141.0*, 140.5*, 139.9, 129.2, 128.9, 128.6*, 128.5*, 128.3, 128.2, 127.6, 126.9*, 126.5, 126.3*, 126.2, 76.4, 75.1 *, 58.2*, 57.9, 44.8, 44.0*, 39.6, 39.3*, 32.9*, 32.8, 32.1, 29.8*, 29.6, 27.0*, 22.8, 15.5*, 14.2, 13.9. FTIR (neat, cm-1): 3369 (br, m, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 23H 29NO (M-H 20t: 335.2251. Found: 335.2257. Analysis: Calcd for C23 H 31 N0 2 : C, 78.15; H, 8.84; N, 3.96. Found: C, 78.12; H, 9.08; N, 3.81. 1LC (80% EtOAc-hexanes), R; 19: 0.60 (UV, PMA). 2: 0.38 (UV, PMA). benzyl bromide: 0.76 (UV, PMA). 72 H3Q ~ N~ I THF, 0 oc OH CH3 4 ~ H39. LOA, LiCI; CH3CH2I N~ I ~ 0 H CH3 CH2CH3 92"/o f1S(S).2SJ-a-Ethyl-N -(2-Hydroxy-1-methyl-2-phenylethyl)-N -methyl 20 Benzeneacetamide 20 A solution of n-butyllithium in hexanes (2.04 M, 10.2 mL, 20.8 mmol, 2.08 equiv) was added via cannula to a suspension of lithium chlo1ide (4.24 g, 100 mmol, 10.0 equiv) and diisopropylamine (3.10 mL, 22.1 mmol, 2.21 equiv) in tetrahydrofuran (35 mL) at -78 °C. The resulting suspension was warmed briefly to 0 OC then was cooled to -78 °C. A solution of amide 4 (2.83 g, 10.0 mmol, 1 equiv) in tetrahydrofuran (50 mL) was added dropwise to the reaction flask via cannula. The reaction mixture was stirred at -78 OC for 1 h, at 0 °C for 10 min, at 23 OC for 4 minutes, and finally was cooled to 0 °C, whereupon ethyl iodide (3.20 mL, 40.0 mmol, 4.00 equiv) was added. The mixture was stirred at 0 °C for 40 min then was quenched by the addition of saturated aqueous ammonium chloride (10 mL). The mixture was partitioned between saturated aqueous ammonium chloride solution (800 mL) and ethyl acetate (100 mL). The aqueous layer was separated and extracted with two 100-mL portions of ethyl acetate. The combined organic fractions were dried over sodium sulfate and were concentrated. Pmification of the residue by flash column chromatography (50% ethyl acetate-hexanes) fumished amide 20 as a colorless oil which slowly solidified (2.85 g, 92%): mp 65-66 °C. Chiral capilla1y GC analysis 43 of the correSponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 20 was of ;:::99% de. 73 (3: 1 rotamer ratio, * denotes minor rotamer peaks) 6.9-7.4 (m, 10H, aromatic), 4.95 (br, 1H, OH), 4.51 (t, 1H, J = 6.9 Hz, CHOH), 4.10 (m, 1H, NCHCH 3), 4.03* (m, 1H, CHOH), 3.82* (m, 1H, NCHCH 3 ), 3.11 (dd, 1H, J = 7.5 Hz, 7.0 Hz, CH 3CH 2 CH), 2.78* (s, 3H, NCH 3 ), 2.48* (m, lH, CH 3CH2CH), 2.25 (m, 1H, one of CH 3CH 2), 2.12 (s, 3H, NCH 3), 1.90* (m, 2H, CH 3CH 2 ), 1.73 (m, 1H, one of CH 3CH 2), 0.98 (d, 3H, J = 6.8 Hz, CH 3CHN), 0.97* {m, 3H, CH 3CH 2), 0.82 (t, 3H, J = 7.3 Hz, CH 3CH 2 ), 0.30* {d, 3H, J = 6.5 Hz, CH 3CHN). C NMR (7 5 MHz, CDC1 3) o: 13 (2: 1 rotamer ratio, * denotes minor rotamer peaks) 175.4, 174.2*, 142.3, 141.3*, 140.5*, 139.6, 128.8, 128.71, 128.68*, 128.3*, 128.2, 127.8, 127.7*, 127.4*, 126.9, 126.7*, 126.6*, 126.3; 76.3, 75.6*, 72.7*, 57.6, 51.8, 51.1*, 28.2, 28.1, 27.4*, 14.4*' 14.0, 12.4, 12.3*. FfiR (neat, cm- 1): 3384 (br, m, OH), 1620 (s, C=O). HRMS (FAB): Calcd for C 20H26 N0 2 (MHt: 312.1965. Found: 312.1962. Analysis: Calcd for C20 H25 N0 2 : C, 77.14; H, 8.09; N, 4.50. Found: C, 77.10; H, 8.19; N, 4.44. 1LC (80% EtOAc-hexanes), R; 20: 0.56 (UV, PMA). 4: 0.44 (UV, PMA). 74 n ~ H39. I OH CH3 LOA, LiCI; Mel THF, 0 oc 7 £1S CS).2S)J-N -(2-Hydroxy-1-methyl-2-phenylethy])-N .2-dimethyl Benzenebutanamide A solution of n-butyllithium in hexanes (2.37 M, 13.3 mL, 31.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (3.84 g, 90.6 mmol, 6.00 equiv) and diisopropylamine (4.82 mL, 34.4 mmol, 2.28 equiv) in tetrahydrofuran (50 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 7 (4.70 g, 15.1 mmol, 1 equiv) in tetrahydrofuran (40 mL, followed by a 2-mL rinse) was added via cannula over 4 min. The reaction mixture was stirred at -78 CC: for 30 min, at 0 CC: for 10 min, at 23 CC: for 3 min, and finally was cooled to 0 °C, whereupon iodomethane (1.88 mL, 30.2 mmol, 2.00 equiv) was added. The mixture was stirred at 0 CC: for 20 min, then was quenched by the addition of saturated aqueous ammonium chloride solution (15 mL) and half-saturated brine (150 mL). The layers were separated, and the aqueous layer was extracted with two 60-mL portions of ethyl acetate. The combined organic extracts were washed with brine (2 x 15 mL), then were dried over sodium sulfate and were concentrated. Recrystallization of the cmde product from hot toluene (110 °C, 13 mL) afforded amide 21 as white crystals (2.76 g, 56%). The mother liquor was concentrated to afford a solid residue, and the solid was recrystallized from hot hexanes (69 °C, 5 mL) to afford additional product as an off-white solid (1.78 g, 36%): mp 89-90 °C. Chiral capillary GC analysis 43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 21 was of ~99% de. 75 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, lOH, aromatic), 4.70 (br, 1H, OH), 4.65 (m, 1H, CHOH), 4.50* (m, 1H, CHOH), 4.30 (m, 1H, NCHCH 3 ), 3.85* (m, 1H, NCHCH 3), 2.93* (s, 3H, NCH 3), 2.65 (s, 3H, NCH 3), 2.5-2.8 (m, 3H, COCH, PhCH 2), 2.05 (m, 1H, one of PhCH 2 CH 2 ), 1.65 (m, 1H, one of PhCH 2CH2 ), 1.21 (d, 3H, J = 7.0 Hz, CH 3CHCO), 1.03 (d, 3H, J = 6.8 Hz, CH 3CHN), 0.94* (d, 3H, J = 6.8 Hz, CH 3CHN). 13 C NMR (75 MHz, CDC1 3) 8: (4:1 rotamer ratio, * denotes minor rotamer peaks) 178.5, 142.6, 141.9, 128.7*, 128.6*, 128.4, 128.3, 128.2*, 127.5, 126.9*, 126.2, 125.8, 76.5, 75.6*, 59.7, 57.7*, 48.2*, 35.9*, 35.6, 35.4, 34.6, 33.4, 27.1*, 19.1*, 17.3, 15.5*, 14.4. FTIR (neat, cm-1): 3374 (br, m, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C 21 H28 N0 2 (MHt: 326.2120. Found: 326.2104. Analysis: Calcd for C 21 H27 N0 2 : C, 77.50; H, 8.36; N, 4.30. Found: C, 77 .20; H, 8.47; N, 4.19. TLC (80% EtOAc-hexanes), R; 21: 0.47 (UV, PMA). 7: 0.39 (UV, PMA). 76 H3 0 CHa N~CHa I OH CHa 5 LOA, LiCI; C6 HsCH 2 Br THF, 0 oc ~ ~H3 0 CH 3 ~t;JYCHa 0 H CH 3 CH 2 CsHs 22 [1S CSl.2SJ-a-(1-Methylethyl)-N -(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl Benzene.propionamide 2 2 A solution of n-butyllithium in hexanes (2.37 M, 16.6 mL, 39.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (4.82 g, 114 mmol, 6.00 equiv) and diisopropylamine (6.06 mL, 43.2 mL, 2.28 equiv) in tetrahydrofuran (50 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 5 (4.73 g, 19.0 mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 3-mL rinse) was added via cannula. The reaction mixture was stitTed at -78 'C for 40 min, at 0 'C for 10 min, at 23 'C for 3 min, and finally was cooled to 0 °C, whereupon benzyl bromide (4.06 mL, 34.1 mmol, 1.80 equiv) was added. The mixture was stirred at 0 °C for 1 h then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was partitioned between half-saturated brine (200 mL) and ethyl acetate (30 mL). The aqueous layer was separated and extracted with two 75-mL portions of ethyl acetate. The combined organic extracts were washed with two 15-mL portions of brine, then were dried over sodium sulfate and were concentrated. The residue was dissolved in hot ethyl acetate (77 °C, 8 mL), and the solution was diluted with hot hexanes (69 °C, 8 mL). Recrystallization of the product from this 1:1 mixture of ethyl acetate and hexanes afforded amide 22 as white crystals (5.36 g, 83%): mp 118-119 °C. Chiral capillary GC analysis 43 of the corresponding ttimethylsilyl ether, prepared as described above for amide 11, established that amide 22 was of ~99% de. 77 (6:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10H, aromatic), 4.40-4.52 (m, 2H, CHOH, NCHCH 3 ), 4.15* (m, 1H, CHOH), 3.85* (m, 1H, NCHCH 3 ), 3.63 (m, 1H, CHOH), 2.86 (m, 2H, CHCH2Ph), 2.76* (s, 2H, CH 2 Ph), 2.74* (s, 3H, NCH 3 ) 2.66 (m, 1H, CHCH 2Ph), 2.49 (s, 3H, NCH 3 ), 2.01 (m, 1H, CH(CH 3) 2 ), 1.09 (d, 3H, J = 6.7, one of CH(CH 3) 2 ), 1.08* (d, 3H, J = 6.7 Hz, one of CH(CH 3) 2), 0.97 (d, 3H, J = 6. 7 Hz, one of CH(CH 3) 2 ), 0.88* (d, 3H, J = 6.7 Hz, one of CH(CH 3 ) 2 ), 0.63 (d, 3H, J = 6.5 Hz, CH 3CHN). C NMR (7 5 MHz, CDC1 3) o: 13 (6: 1 rotamer ratio, * denotes minor rotamer peaks) 177.6, 142.2, 141.0*, 140.2, 129.2*, 128.9, 128.6*, 128.5*, 128.3, 128.2, 127.6, 127.0*, 126.6, 126.5*, 126.1, 76.5, 75.0*, 58.2*, 57.1, 52.2, 51.0*, 37.1, 36.8*, 31.6, 31.5*, 31.2, 27.0*, 21.3, 20.3*, 20.1, 15.2*, 14.1. FTIR (neat, cm-1): 3381 (br, s, OH), 1614 (s, C=O). HRMS (FAB): Calcd for C22 H30 N0 2 (MHt: 340.2277. Found: 340.2292. Analysis: Calcd for C 22 H 29 N0 2 : C, 77.84; H, 8.61; N, 4.13; Found: C, 77.49; H, 8.81; N, 4.03. 1LC (60% EtOAc-hexanes), R_r 22: 0.41 (UV, PMA). 5: 0.23 (UV, PMA). benzyl bromide: 0.64 (UV, PMA). 78 LOA, LiCI; C5HsCH 2 Br THF, 0 oc 84% f 1SCS).2Sl-a-(1. 1-Dimethylethyl)-N-(2-hydroxy-1-methyl-2-phenylethyl)-N -methyl Benzenepropionamide 2 3 A solution of n-butyllithium in hexanes (2.37 M, 15.4 mL, 36.6 mmol, 2.08 equiv) was added to a suspension of lithium chloride (4.47 g, 106 mmol, 6.00 equiv) and diisopropylamine (5.62 mL, 40.1 mmol, 2.28 equiv) in tetrahydrofuran (60 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 6 (4.63 g, 17.6 mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 3-mL rinse) was added via cannula over 4 min. The resulting mixture was stirred at -78 OC for 30 min, at 0 OC for 10 min, at 23 OC for 3 min, and finally was cooled to 0 CC whereupon benzyl bromide (4.60 mL, 38.7 mmol, 2.20 equiv) was added. The mixture was stirred at 0 OC for 2.8 h, then was quenched by the addition of saturated aqueous ammonium chloride solution (10 mL). The mixture was partitioned between half-saturated brine (200 mL) and ethyl acetate (30 mL), and the aqueous layer was separated and extracted with two 75-mL portions of ethyl acetate. The combined organic extracts were washed with two 15-mL portions of brine, then were d1ied over sodium sulfate and were concentrated. Recrystallization of the crude product from hot toluene (110 °C, 25 mL) afforded amide 23 as white crystals (5.24 g, 84%): mp 125-127 °C. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as desc1ibed above for amide 11, established that amide 23 was of ~99% de. 79 H NMR (300 MHz, CDC1 3) o: 1 (7:1 rotamer ratio, * denote minor rotamer peaks) 7.15-7.35 (m, lOH, aromatic), 4.40-4.52 (m, 2H, CHOH, NCHCH 3 ), 3.9-4.1 * (m, 2H, CHOH, NCHCH 3), 2.75-3.0 (m, 3H, PhCH 2CH), 2.69* (s, 3H, NCH 3 ), 2.48 (s, 3H, NCH 3), 1.11 (s, 9H, C(CH 3) 3 ), 1.08* (s, 9H, C(CH 3) 3 ), 0.86* (d, 3H, J = 6.6 Hz, CH 3 CHN), 0.60 (d, 3H, J = 6.4 Hz, CH 3CHN). C NMR (7 5 MHz, CDC13) o: 13 (7:1 rotamer ratio, * denotes minor rotamer peaks) 177.1, 142.1, 140.6, 129.2*, 128.8, 128.7*, 128.3, 128.2, 127.6, 127.0*, 126.7, 128.1 *, 126.1, 76.4, 74.9*, 58.5*, 57.0, 54.2, 53.8*, 35.6*, 35.2, 33.8*, 31.8, 28.1 *, 27.0, 26.8, 19.2*, 15.0*, 14.2. FTIR (neat, cm-1): 3393 (br, m, OH), 1615 (s, C=O). HRMS (FAB): Calcd for C 23 H32 N0 2 (MHt: 354.2433. Found: 354.2439. Analysis: Calcd for C23H 31 N0 2 : C, 78.15; H, 8.84; N, 3.96. Found: C, 78.08; H, 8.90; N, 3.85. TLC (60% EtOAc-hexanes), R; 23: 0.52 (UV, PMA). 6: 0.33 (UV, PMA). benzyl bromide: 0.69 (UV, PMA). 80 H3JLC-?I NI OH CH3 :::::,...N LOA, LiCI; CH2=CHCH2l THF, -78 oc 9 Oyt~JlP 0 H CH3 CH2CH=CH2 83"/o 24 r1SCS).2SJ-a-Allyl-N-(2-hydroxy-1-methyl-2-phenylethyn-N-methyl 3-Pyridineacetamide A solution of n-butyllithium in hexanes (2.34 M, 0.890 mL, 2.08 mmol, 2.08 equiv) was added to a suspension of lithium chloride (254 mg, 6.00 mmol, 6.00 equiv) and diisopropylamine (0.320 mL, 2.28 mmol, 2.28 equiv) in tetrabydrofuran (3.0 mL) at -78 °C. The resulting suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of amide 9 (284 mg, 1.00 mmol, 1 equiv) in tetrahydrofuran (5.0 mL, followed by a 0.5 mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 30 min, at 0 °C for 10 min, then was cooled to -78 °C, whereupon allyl iodide (0.229 mL, 2.50 mmol, 2.50 equiv) was added. The mixture was stirred at -78 'C for 3.8 h then was quenched by the addition of a solution of acetic acid in methanol (40% v/v, 0. 7 mL). The mixture was warmed to 23 °C, and traces of iodine were removed by the addition of 2M aqueous sodium thiosulfate solution (5 mL). The mixture was partitioned between half-saturated sodium bicarbonate solution (50 mL) and ethyl acetate (15 mL). The aqueous layer was separated and extracted with two 15-mL pmtions of ethyl acetate. The combined organic fractions were washed with brine (5 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes-uiethylamine [(85: 15:2) -+ (95:5:2)] afforded amide 24 as a yellow solid (268 mg, 83% ). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as desc1ibed above for amide 11, established that amide 24 was of 98% de. 81 1 H NMR (300 MHz, CDC13) S: (2: 1 rotamer ratio, * denotes minor rotamer peaks) 8.4-8.6 (m, 2H, two of C 5 H 4N), 7.65 (m, 1H, one of C 5H 4N), 7.15-7.4 (m, 6H, one of C 5H 4N, phenyl), 5.70 (m, 1H, CH=CH 2 ), 5.00 (m, 2H, CH=CH2 ), 4.6-4.8 (m, 2H, CHOH, NCHCH 3), 4.03 (m, 1H, COCH), 3.74* (t, 1H, J = 7.3 Hz, COCH), 2.92 (s, 3H, NCH 3), 2.83 (m, 2H, CH 2CH=CH 2 ), 2.77 (s, 3H, NCH 3), 2.38* (m, 2H, CH2 CH=CH2 ), 1.10 (d, 3H, J = 6.6 Hz, CH 3), 0.60* (d, 3H, J = 6.7 Hz, CH 3). 13 C NMR (7 5 MHz, CDC13) S: (2: 1 rotamer ratio, * denotes minor rotameric peaks) 173.4, 172.7*, 149.5, 149.4*, 148.4, 148.2*, 142.1, 141.5*, 135.61 *, 135.58*, 135.3, 135.2, 135.1 *, 134.7, 128.8, 128.34*, 128.27, 127.6, 126.6, 126.2, 123.9, 123.7*, 117.2, 117.0*, 76.1, 75.3*, 57.9, 46.8, 46.2*, 39.0, 38.8*, 27.6, 14.9*, 14.1. FTIR (neat, cm-1): 3388 (br, m, OH), 1633 (s, C=O). HRMS (FAB) Calcd for C 20H 25 N2 0 2 (MHY: 325.1916. Found: 325.1918. Analysis: Calcd for C20H 24 N 2 0 2 : C, 74.05; H, 7.46; N, 8.63. Found: C, 73.91; H, 7.34; N, 8.58. lLC (E~N-pretreated plate, 80% EtOAc-hexanes), R;. 24: 0.57 (UV, PMA). 9: 0.36 (UV, PMA). allyl iodide: 0.09 (PMA). 82 QX~ .:: I OH CH3 8 LDA, LiCI; CH3I THF, -78 oc 88"/o ~ <;:H3YyOr~ ~N S .:: I OH CH3 CH3 25 UR<R).2Rl-N -(2-Hydroxy-1-methyl-2-pheny1ethyn-N.2-dimethy1 2-Thiopheneacetamide A solution of n-butyllithium in hexanes (2.34 M, 6.31 mL, 14.8 mmol, 2.08 equiv) was added to a suspension of lithium chloride (1.96 g, 46.2 mmol, 6.50 equiv) and diisopropylamine (2.27 mL, 16.2 mmol, 2.28 equiv) in tetrahydrofuran (15 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 8 (2.06 g, 7.10 mmol, 1 equiv) in tetrahydrofuran (15 mL, followed by a 3-mL rinse) was added via cannula. The resulting mixture was stirred at -78 OC for 30 min, at 0 °C for 10 min, and finally was cooled to -78 °C, whereupon iodomethane (1.55 mL, 24.9 mmol, 3.50 equiv) was added. The reaction mixture was stin·ed at -78 OC for 7.7 h then was quenched by the addition of a solution of acetic acid in ether (30% v/v, 4.4 mL). The mixture was warmed to 23 °C, then was diluted with 2 M aqueous sodium thiosulfate solution (5 mL) and was partitioned between 2 M aqueous sodium thiosulfate solution (150 mL) and ethyl acetate (50 mL). The aqueous layer was separated and extracted with two 75-mL portions of ethyl acetate. The combined organic extracts were washed with brine (10 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (50% ethyl acetate-hexanes) afforded amide 25 as a yellow oil (1.90 g, 88%). Chiral capillary GC analysis 43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 25 was of 95% de. 83 (2:1 rotarner ratio, * denotes minor rotarner peaks) 7.10---7.42 (rn, 5H, phenyl), 6.8-7.0 (rn, 3H, thiophene), 4.57 (rn, 1H, CHOH), 4.44 (rn, 1H, NCHCH 3), 4.16 (rn, 1H, COCH), 2.95* (s, 3H, NCH 3 ), 2.82 (s, 3H, NCH 3 ), 1.49 (d, 3H, J = 6.8 Hz, CH 3 ), 1.49* (d, 3H, CH 3 ), 1.33 (d, 3H, J = 6.9 Hz, CH 3 ), 0.76* (d, 3H, J = 6.7 Hz, CH 3 CHN). (2:1 rotarner ratio,* denotes rotarner peaks) 175.1, 144.0*, 142.3, 128.8, 128.3, 128.1 *, 127 .6, 127.1 *, 126.7, 126.4, 124.6*, 124.4*, 124.2, 124.0*, 123.9*, 76.4, 75.7*, 59.2, 58.1 *, 39.0, 38.1 *, 33.1, 27.5*, 21.2, 14.9*, 14.0. FTIR (neat, crn-1): 3386 (br, rn, OH), 1625 (s, C=O). HRMS (FAB): Calcd for C 17H 22N0 2 S (MH/: 304.1371. Found: 304.1368. 1LC (80% EtOAc-hexanes), R; 25: 0.48 (UV, PMA). 8: 0.39 (UV, PMA). 84 01 H3 0 N~CHs I THF, ooc OH CH 3 1 89"/o ~Ha 0 ~t;J~CHs 0 H CH 3 CH 3 CHs 26 flS (R).2SJ-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N,2,4-trimethyl Pentanamide 2 6 A solution of n-butyllithium in hexanes (2.37 M, 10.7 mL, 25.4 mmol, 2.08 equiv) was added to a suspension of lithium chloride (3.10 g, 73.2 mmol, 6.00 equiv) and diisopropylamine (3.90 mL, 27.8 mmol, 2.28 equiv) in tetrahydrofuran (50 mL) at-78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (2.70 g, 12.2 mmol, 1 equiv) in tetrahydrofuran (40 mL, followed by a 2-mL rinse) was added via cannula over 4 min. The resulting mixture was stirred at -78 °C for 1 h, at 0 °C for 10 min, at 23 °C for 3 min, and finally was cooled to 0 °C whereupon isobutyl iodide (5.62 mL, 48.8 mmol, 4.00 equiv) was added. After 6 h, the reaction was quenched by the sequential addition of saturated aqueous ammonium chloride solution (15 mL) and 2M aqueous sodium thiosulfate solution (5 mL). The mixture was partitioned between half-saturated brine (150 mL) and ethyl acetate (30 mL), and the aqueous layer was separated and extracted with two 60-mL portions of ethyl acetate. The combined organic fractions were washed with two 15-mL portions of brine, then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (25 -t 47%) afforded amide 26 as a white solid (2.99 g, 89% ). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 26 was of 98% de. A portion of the recovered solid (2.93 g) was recrystallized from hot hexanes (69 °C, 8 mL) to afford amide 26 as white crystals (2.16 g, 74% recovery, 65% overall yield): mp 59-60 °C. 85 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.2-7.4 (m, 5H, aromatic), 4.60 (m, 1H, CHOH), 4.38 (br, 1H, NCHCH3 ), 4.10* (m, 1H, NCHCH 3), 2.93* (m, 1H, COCHCH3), 2.91 * (s, 3H, NCH3 ), 2.85 (s, 3H, NCH 3), 2.67 (sx, 1H, J = 6.8 Hz, COCHCH3 ), 1.77 (m, 1H, CH(CH 3) 2), 1.5 (m, 2H, CH2 ), 1.15 (d, 3H, J = 7.0 Hz, CH 3 ), 1.07 (d, 3H, J = 6.7 Hz, CH 3 ), 0.88-1.02* (m, 6H, CH(CH3 ) 2), 0.85 (d, 3H, J = 6.2 Hz, CH 3 ), 0.82 (d, 3H, J = 6.5 Hz, CH 3). (4:1 rotamer ratio, * denotes minor rotamer peaks) 179.3, 142.6, 128.7*, 128.2, 127.4, 126.9*' 126.3, 76.5, 75.3*, 59.2, 58.0*, 43.1, 34.4, 33.5*, 33.2, 26.2*, 25.6, 23.0*, 22.7, 22.5, 18.1*, 17.4, 15.4*, 14.4. FTIR (neat, cm-1): 3385 (br, s, OH), 1619 (s, C=O). HRMS (FAB): Calcd for C 17H28 N0 2 (MHt: 278.2120. Found: 278.2109. Analysis: Calcd for C 17H 27N0 2 : C, 73.61; H, 9.81; N, 5.05. Found: C, 73.65; H, 10.02; N, 4.94. TLC (80% EtOAc-hexanes), R; 26: 0.54 (UV, PMA). 1: 0.27 (UV, PMA). 86 LOA, LiCI; I~CH3 CH3 THF, 23 oc 94% [1SC2R.4S).2SJ-N-C2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4-tlimethyl Hexanamideamide 2 7 A solution of n-butyllithium in hexanes (2.44 M, 7.54 mL, 18.4 mmol, 3.67 equiv) was added via cannula to a suspension of lithium chl01ide (2.81 g, 66.2 mmol, 13.2 equiv) and diisopropylamine (2.72 mL, 19.4 mmol, 3.86 equiv) in tetrahydrofuran (15 mL) at -78 °C. The resulting suspension was wanned b1iefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (2.09 g, 9.45 mmol, 1.88 equiv) in tetrahydrofuran (30 mL, followed by a 3-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 30 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon (S)1-iodo-2-methylbutane (994 mg, 5.02 mmol, 1 equiv) was added. The mixture was stirred for 20 h at 23 OC then was quenched with half-saturated aqueous ammonium chloride solution (40 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (25 ~ 47%) furnished amide 27 as an oil which slowly solidified (1.38 g, 94%): mp 49-51 °C. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that the ratio of the (2R ,4S) diastereomer to the (2S ,4S) diastereomer was 62: 1. 87 (5: 1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 5H, aromatic), 4.55 (t, 1H, J = 7.3 Hz, CHOH), 4.13 (m, 1H, NCHCH 3 ), 3.94* (m, 1H, NCHCH 3), 2.99* (m, 1H, COCH), 2.75* (s, 3H, NCH 3 ), 2.35 (m, 1H, COCH), 2.23 (s, 3H, NCH 3), 1.98* (m, IH, CH3 CH 2CH), 1.50 (m, 3H, COCHCH2, CH 3CH 2CH), 1.20 (m, 2H, CH 3CH 2), 0.90-1.04 (m, 6H, COCHCH 3, CH 3CH 2CHCH 3), 0.74-0.82 (m, 6H, CH 3CH 2 , CH 3CHN), 0.62* (d, 3H, J = 6.7 Hz, CH 3 CHN). C NMR (100 MHz, CDC1 3) o: 13 (5: 1 rotamer ratio, * denotes minor rotamer peaks) 178.3, 177.1 *, 141.5, 140.2*, 127.6*, 127.1, 126.3, 125.8*, 125.2, 75.4, 74.2*, 58.2, 57.0*, 39.6, 33.1' 32.1' 30.9, 28.9*' 28.5, 25.8*' 17 .9, 16.5*, 15.9, 14.4*, 13.3, 10.1. FTIR (neat, cm-1) 3385 (br, m, OH), 1618 (s, C=O). HRMS (EI): Calcd for C 18 H30 N0 2 (MHt: 292.2277. Found: 292.2272. Analysis: Ca1cd for C 18 H 29 N0 2 : C, 74.18; H, 10.03; N, 4.81. Found: C, 74.22; H, 9.75; N, 4.80. 1LC (80% EtOAc-hexanes), R; 27: 0.50 (UV, PMA). 1: 0.33 (UV, PMA). 88 ~ 9H30 ~N~CH3 .: I OH CH3 ent-1 LDA, LiCI; I~CH3 CH3 THF, 23 oc 94% [1R(2S.4S).2Rl-N-C2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4-trimethy1 Hexanamide 28 A solution of n-butyllithium in hexanes (2.44 M, 7.40 mL, 18.1 mmol, 3.64 equiv) was added via cannula to a suspension of lithium chlmide (2.75 g, 64.9 mmol, 13.1 equiv) and diisopropylamine (2.67 mL, 19.0 mmol, 3.84 equiv) in tetrahydrofuran (15 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An icecooled solution of ent-1 (2.09 g, 9.45 mmol, 1.88 equiv) in tetrahydrofuran (30 mL, followed by a 2-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 30 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon (S)1-iodo-2-methylbutane (983 mg, 4.96 mmol, 1 equiv) was added. The mixture was stirred at 23 °C for 18 h then was quenched by the addition of half-saturated aqueous ammonium chloride solution (40 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (25 --+ 47%) furnished amide 28 as a viscous oil (1.35 g, 94%). Amide 28 (16 mg, 0.055 mmol, 1 equiv) was acetylated with acetic anhydride (18 )lL, 0.19 mmol, 3.5 equiv) and 4dimethylaminopyridine (24 mg, 0.19 mmol, 3.5 equiv) in dichloromethane (1 mL) at 23 'C for 1 h. Chiral capillary GC analysis43 of the resulting acetate ester established that the ratio of the (2S,4S) diastereomer to the (2R,4S) diastereomer was 89:1. 89 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.0--7.4 (m, 5H, aromatic), 5.2 (br, 1H, OH), 4.54 (t, 1H, J = 7.2 Hz, CHOH), 4.15 (m, 1H, NCHCH 3), 3.95* (m, 1H, NCHCH 3), 3.05* (m, 1H, COCH), 2.74* (s, 3H, NCH 3), 2.45 (m, 1H, COCH), 2.25 (s, 3H, NCH 3 ), 1.89 (m, 1H, CH3CH2CH), 1.62* (m, 1H, CH3CH2CH), 1.48* (m, 2H, CH 3 CH2 CHCH 2), 1.28 (m, 2H, CH 3CH2 CHCH2 ), 1.08* (d, 3H, J = 9.2 Hz, COCHCH3), 1.04* (d, 3H, J = 6.4 Hz, CH 3 CH2 CHCH3 ), 1.01 (d, 3H, J = 6.5 Hz, COCHCH3 ), 0.97 (d, 3H, J = 7.1 Hz, CH3 CHN), 0.88 (t, 3H, J = 7.2 Hz, CH 3CH 2), 0.70 (d, 3H, J = 6.8 Hz, CH 3CH2 CHCH 3), 0.63* (d, 3H, J = 6.4 Hz, CH 3 CHN). 13 C NMR (100 MHz, CDClJ 8: (4:1 rotamer ratio, * denotes minor rotamer peaks) 179.3, 177.9*, 142.7, 141.3*, 128.8*, 128.3, 128.1, 127.6, 127.0*, 126.3, 76.6, 75.3*, 59.2, 58.1*, 41.3, 34.3, 33.8*, 33.4, 32.1, 29.7, 26.9*, 19.5*, 19.2, 18.8*, 18.0, 15.5*, 14.5, 11.2. FTIR (neat, cm-1): 3384 (br, m, OH), 1618 (s, C=O). HRMS (EI): Calcd for C 18 H30 N0 2 (MHt: 292.2277. Found: 292.2268. 1LC (80% EtOAc-hexanes), R; 28: 0.50 (UV, PMA). ent-1: 0.33 (UV, PMA). 90 LOA, LiCI; I~Fh CH 3 THF, 23 oc 97"/o [ lS (2R .4S).2Sl-N-(2-Hydroxy-l-methyl-·-phenylethyll-N.2.4-tri methyl Benzene- pentanamide 2 9 A solution ofn-butyllithium in hexanes (2.33 M, 28.8 mL, 67.1 mmol, 3.90 equiv) was added via cannula to a suspension of lithium chloride (9.20 g, 217 mmol, 12.6 equiv) and diisopropylamine (10.6 mL, 75.7 mmol, 4.40 equiv) in tetrahydrofuran (45 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An icecooled solution of amide 1 (8.00 g, 36.2 mmol, 2.10 equiv) in tetrahydrofuran (115 mL, followed by a 5-mL rinse) was added dropwise via cannula. The mixture was stirred at -78 °C for 40 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 67 (4.48 g, 17.2 mmol, 1 equiv) in tetrahydrofuran (3 mL, followed by a 3-mL rinse) was added via cannula. The mixture was stirred at 23 °C for 6 h then was quenched by the addition of75% saturated aqueous ammonium chloride solution (200 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 100 mL). The combined organic fractions were washed with brine (30 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (48% ethyl acetate-hexanes) furnished amide 29 as a viscous oil (5.89 g, 94%). The ratio of the (2R,4S) diastereomer to the (2S,4S) diastereomer was estimated to be ~99: 1 based on the crude de of the reduction product 61 (vide infra). 91 H NMR (400 MHz, CDC13) o: 1 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10H, aromatic), 4.95 (br, 1H, OH), 4.57 (m, 1H, CHOH), 4.51 * (m, 1H, CHOH), 4.39 (br, 1H, NCHCH3), 4.1 * (m, 1H, NCHCH 3), 3.34 (br, 1H, H2), 3.04* (m, 1H, H2), 2.86* (s, 3H, NCH 3 ), 2.76 (s, 3H, NCH 3 ), 2.66 (m, 2H, PhCH2 ), 2.25 (m, 1H, H4), 1.97* (m, 2H, PhCH2 ), 1.78 (m, 1H, one of H3), 1.71 (m, 1H, one of H3), 1.21 * (m, 2H, H3), 1.10 (d, 3H, J = 7.0 Hz, H1), 1.06* (d, 3H, J = 7.0 Hz, H1), 1.02 (d, 3H, J = 7.0 Hz, CH 3 CHN), 0.97* (d, 3H, J = 6.6 Hz, H5), 0.83* (d, 3H, J = 6.6 Hz, CH 3CHN), 0.70 (d, 3H, J = 6.6 Hz, H5). (4:1 rotamer ratio, * denotes minor rotamer peaks) 178.4, 177.2*, 142.5, 141.6*, 141.1 *, 140.8, 129.1 *, 129.0, 128.4*, 128.0, 127.9, 127.2, 126.7*, 126.3*, 126.1, 125.6, 125.4*, 76.1, 75.0*, 58.7, 57.8*, 43.7, 43.5*, 41.5*, 41.2, 34.1, 33.2*, 33.0, 32.4, 26.9*, 19,3*, 19.2, 18.6*, 17.7, 15.4*, 14.1. FTIR (neat, cm-1): . 3384 (br, m, OH), 1620 (s, C=O). Analysis: Calcd for C23 H31 N02 : C, 78.15; H, 8.84; N, 3.96. Found: C, 77.99; H, 9.00; N, 3.91. TLC (30% EtOAc-hexanes), R; 29: 0.14 (UV, PMA). 67: 0.68 (UV, PMA). 92 LOA, LiCI; ~~Ph OH THF, 23 oc CH3 CH 3 CHs 29 90% [1 S (2R .4S). 2SJ-N-(2-Hydroxy-l-methyl-2-phenylethy1)-N.2.4-trimethyl Benzene- pentanamide 2 9 Amide 29 could also be prepared using fewer equivalents of enolate. Thus a solution of n-butyllithium in hexanes (0.933 mL, 2.27 mmol, 2.65 equiv) was added via cannula to a suspension of lithium chloride (343 mg, 8.09 mmol, 9.45 equiv) and diisopropylamine (0.342 mL, 2.44 mmol, 2.85 equiv) in tetrahydrofuran (1.5 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (256 mg, 1.15 mmol, 1.35 equiv) in tetrahydrofuran (3 mL, followed by a 1-mL rinse) was added dropwise via cannula. The mixture was stirred at -78 CC for 40 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 67 (223 mg, 0.855 mmol, 1 equiv) in tetrahydrofuran (1 mL, followed by a 1-mL rinse) was added via cannula. The mixture was stirred at 23 CC for 21 h then was quenched by the addition of75% saturated aqueous ammonium chloride solution (20 mL). The mixture was extracted with ethyl acetate (3 x 10 mL). The combined organic fractions were washed with brine (5 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (48% ethyl acetate-hexanes) furnished amide 29 as a viscous oil (272 mg, 90% ). The ratio of the (2R,4S) diastereomer to the (2S,4S) diastereomer was estimated to be 99:1 based on the crude de of the reduction product 61 (vide infra). Spectroscopic data were identical to those listed above. 93 ~ 9H 3 0 ~~CHs N : I OH CHs LOA, LiCI; I~A1 CH 3 ent-1 THF, 23°C 95% [lR C2S .4S).2R1-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4-trimethyl Benzene- pentanamide 3 0 A solution of n-butyllithium in hexanes (2.33 M, 26.2 mL, 60.9 mmol, 4.05 equiv) was added via cannula to a suspension oflithium chloride (9.20 g, 217 mmol, 14.4 equiv) and diisopropylamine (9.56 mL, 68.2 mmol, 4.53 equiv) in tetrahydrofuran (40 mL) at .,...78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An icecooled solution of ent-1 (6.89 g, 31.1 mmol, 2.07 equiv) in tetrahydrofuran (115 mL, followed by a 3 mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 40 min, at 0 OC for 10 min, and at 23 OC for 3 minutes, whereupon a solution of the iodide 67 (3.92 g, 15.1 mmol, 1 equiv) in tetrahydrofuran (4 mL, followed by a 2-mL rinse) was added via cannula. The mixture was stirred at 23 °C for 7 h then was quenched by the addition of 75% saturated aqueous ammonium chloride solution (200 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 120 mL). The combined organic fractions were washed with brine (40 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (47 ~51%) furnished amide 30 as a viscous oil (5.05 g, 95%). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that the ratio of the (2S,4S) diastereomer to the (2R,4S) diastereomer was 58:1. 94 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10H, aromatic), 4.79 (br, lH, OH), 4.54 (m, 1H, CHOH), 4.50* (m, 1H, CHOH), 4.45 (m, 1H, NCHCH3 ), 4.05* (m, 1H, NCHCH3 ), 3.36 (br, lH, H2), 2.96* (m, lH, H2), 2.87* (s, 3H, NCH 3 ), 2.75 (s, 3H, NCH 3 ), 2.58 (m, 2H, one o_f PhCH 2 ), 2.33 (dd, 1H, J 1 = 13.2 Hz, 12 = 8.1 Hz, one of PhCH2 ), 1.79* (m, 1H, H4), 1.67 (m, 1H, H4), 1.46 (m, 1H, one of H3), 1.33 (m, 1H, one of H3), 1.08 (d, 3H, J = 6.6 Hz, H1), 1.02* (d, 3H, J = 6.6 Hz, H1), 0.97 (d, 3H, J = 6.6 Hz, CH 3 CHN), 0.81 (d, 3H, J = 6.6 Hz, H5). 13 C NMR (100 MHz, CDCIJ 8: (4:1 rotamer ratio, * denotes minor rotamer peaks) 178.6, 177.6*, 142.5, 141.6*, 141.1 *, 140.8, 129.1 *, 128.9, 128.4*, 128.03, 128.00, 127.3, 126.7*, 126.2, 125.6, 125.4*, 76.1, 75.1 *, 58.2, 57.8*, 43.8, 40.8, 40.5, 34.2, 33.1*, 32.7, 32.4*, 26.9*, 19.6, 19.1 *, 17.5*, 17.0, 15.4*, 14.2. FTIR (neat, cm-1): 3385 (br, m, OH), 1618 (s, C=O). Analysis: Calcd for C23H 31 N0 2 : C, 78.15; H, 8.84; N, 3.96. Found: C, 78.27; H, 8.94, N, 3.97. 1LC (30% EtOAc-hexanes), R; 30: 0.18 (UV, PMA). 67: 0.72 (UV, PMA). 95 H3 0 Njl_,CH3 1 OH CH3 1 LOA, LiCI; I~A1 CH3 CH3 THF, 23°C 93"/o [1S(2R .4R. 6S). 2S]-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4.6-tetramethyl Benzeneheptanamide 3 1 A solution of n-butyllithium in hexanes (2.43 M, 5.30 mL, 12.9 mmol, 3.88 equiv) was added via cannula to a suspension of lithium chloride (1.77 g, 41.7 mmol, 12.5 equiv) and diisopropylamine (2.04 mL, 14.6 mmol, 4.38 equiv) in tetrahydrofuran (9 mL) at -78 °C. The suspension was warmed briefly to 0 °C then was cooled to -78 °C. An ice-cooled solution of amide 1 (1.47 g, 6.65 mmol, 2.00 equiv) in tetrahydrofuran (25 mL, followed by a 3-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 40 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 68 (LOO g, 3.32 mmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 3-mL rinse) was added. The mixture was stirred at 23 OC for 18 h then was quenched by the addition of half-saturated aqueous ammonium chloride solution (50 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with brine (7 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (39% ethyl acetate-hexanes) furnished amide 31 as a viscous oil (1.22 g, 93%). Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that the ratio of the (2R,4R,6S) diastereomer to the (2S,4R,6S) diastereomer was 142:1. 96 1 H NMR (400 MHz, CDC13) 8: (3:1 rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, 10H, aromatic), 4.97 (br, 1H, OH), 4.49 (m, 1H, CHOH), 4.46 (m, 1H, NCHCH 3), 4.02* (m, 1H, CHOH), 3.82* (m, 1H, NCHCH 3), 2.94* (m, 1H, H2), 2.81 * (s, 3H, NCH 3 ), 2.73 (s, 3H, NCH 3 ), 2.65 (m, 1H, H2), 2.59 (m, 1H, one of H9), 2.28 (m, 1H, one of H9), 1.85 (m, 2H, H7, H4), 1.75 (m, 1H, one of H3), 1.59* (m, 2H, H3), 1.47 (m, 1H, one of H3), 1.29* (m, 2H, H6), 1.20 (m, 2H, H6), 1.04 (d, 3H, J = 6.2 Hz, H1), 1.00* (d, 3H, J = 6.6 Hz, H1), 0.94 (d, 3H, J = 6.6 Hz, CHNCH 3), 0.83 (d, 3H, J = 6.2 Hz, H8), 0.76 (d, 3H, J = 6.6 Hz, H5). 13 C NMR (100 MHz, CDC13) 8: (3:1 rotamer ratio, * denotes minor rotamer peaks) 178.2, 177.2*, 142.4, 141.7*, 141.2*, 141.0, 128.9, 128.2*, 127.8, 127.7, 127.0, 126.6*, 126.0, 125.3, 75.7, 74.8*, 57.6, 44.9*, 44.6, 43.3, 43.1, 41.2*, 40.8, 33.5, 32.8*, 32.3*, 31.9, 27.8, 26.8*, 20.5*, 20.3, 20.0*, 19.8, 18.5*, 17.8, 15.2*, 14.0. FTIR (neat, cm-1): 3383 (br, m, OH), 1621 (s, C=O). HRMS (FAB): Calcd for C26H 38 N0 2 (MHt: 396.2903. Found: 396.2897. TLC (30% EtOAc-hexanes), R; 31: 0.17 (UV, PMA). 68: 0.66 (UV, PMA). 97 ~ 9H 3 0 ~ j(__cHs - N : I OH CH 3 ent-1 LOA, LiCI; I~A1 CHs CHs THF, 23 oc 93% [1R(2S .4R. 6S).2R]-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4.6-tetramethyl Benzeneheptanamide 3 2 A solution ofn-butyllithium in hexanes (2.43 M, 5.31 mL, 12.9 mmol, 3.87 equiv) was added via cannula to a suspension of lithium chloride (1.77 g, 41.7 mmol, 12.5 equiv) and diisopropylamine (2.04 mL, 14.6 mmol, 4.37 equiv) in tetrahydrofuran (9 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of ent-1 (1.47 g, 6.66 mmol, 2.00 equiv) in tetrahydrofuran (25 mL, followed by a 3-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 'C for 40 min, at 0 OC for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 68 (1.01 g, 3.33 mmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 3-mL rinse) was added. The mixture was stirred at 23 OC for 18 h then was quenched by the addition of half-saturated aqueous ammonium chloride solution (50 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with brine (7 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (39% ethyl acetate-hexanes) furnished amide 32 as a viscous oil (1.27 g, 96%). Chiral capillary GC analysis43 of the corresponding trirnethylsilyl ether, prepared as described above for amide 11, established that the ratio of the (2S,4R,6S) diastereomer to the (2R,4R,6S) diastereomer was 70:1. 98 (3:I rotamer ratio, * denotes minor rotamer peaks) 7.0-7.4 (m, IOH, aromatic), 4.83 (br, IH, OH), 4.53 (m, IH, CHOH), 4.47 (m, IH, NCHCH 3), 4.03* (m, IH, CHOH), 3.62* (m, IH, NCHCH 3), 2.94* (s, 3H, NCH3 ), 2.85 (s, 3H, NCH3 ), 2.62 (m, lH, H2), 2.23 (m, 2H, H9), 1.79 (m, 2H, H7, H4), 1.62* (m, 2H, H7, H4), L5I (m, 2H, H3), 1.33* (m, 2H, H3), 1.20 (m, 2H, H6), 1.05 (d, 3H, J = 7.0 Hz, HI), 0.98 (d, 3H, J = 6.6 Hz, CH 3CHN), 0.89* (d, 3H, J = 6.2 Hz, HI), 0.83 (d, 3H, J = 6.6 Hz, H8), 0.80 (d, 3H, J = 6.6 Hz, H5). 13 C NMR (IOO MHz, CDC13) 8: (3:I rotamer ratio, * denotes minor rotamer peaks) 178.7, I77.8*, I42.3, I41.7*, I41.2*, I41.0, I28.9, I27.I, I26.6*, I28.3*, I27.9, I27.8, I26.I, 125.4, I25.3*, 75.9, 75.0*, 57.7, 45.3*, 44.9, 43.4, 40.5, 40.0*, 33.8, 32.7*, 32.3, 32.0, 31.8*, 27.6, 27.2*, 26.9*, 20.0, I9.7, I9.5*, I6.5, I5.3*, I4.1. FI1R (neat, cm-1): 3382 (br, m, OH), I620 (s, C=O). HRMS (FAB): Calcd for C26H38 N0 2 (MHt: 396.2903. Found: 396.2890. TLC (30% EtOAc-hexanes), R; 32: O.I7 (UV, PMA). 68: 0.7I (UV, PMA). NJl..._,CHs I OH CH 3 3¥0069 LOA, LiCI; H I~Al Nl H3 0 1 CH 3 CHs THF, 23 oc 99 0 2 4 ~ 7 A1 0 H CH 3 CH 3 CH 3 CH 3 1 5 8 33 93"/o f1S(2R AS. 6S).2SJ-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.2,4, 6-tetramethyl Benzeneheptanamide 3 3 A solution of n-butyllithium in hexanes (2.33 M, 5.53 mL, 12.9 mmol, 3.62 equiv) was added via cannula to a suspension of lithium chloride (1.76 g, 41.6 mmol, 11.7 equiv) and diisopropylamine (2.04 mL, 14.5 mmol, 4.09 equiv) in tetrahydrofuran (9 mL) at -78 oc_ The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (1.53 g, 6.93 mmol, 1.95 equiv) in tetrahydrofuran (24 mL, followed by a 5-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 °C for 40 min, at 0 °C for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 69 (L07 g, 3.56 mmol, 1 equiv) in tetrahydrofuran (3 mL, followed by a 2-mL rinse) was added. The mixture was stirred at 23 OC for 12 h then was quenched by the addition of half-saturated aqueous ammonium chloride solution (30 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with brine (7 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (44% ethyl acetate-hexanes) furnished amide 33 as a white solid (1.30 g, 96%): mp 73-74 °C. Chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that the ratio of the (2R,4S,6S) diastereomer to the (2S,4S,6S) diastereomer was 66:1. 100 H NMR (400 MHz, CDC13) o: 1 (3:1 rotamer ratio, * denotes minor rotamer peaks) 7.0--7.4 (m, 10H, aromatic), 4.58 (m, 1H, CHOH), 4.54* (m, 1H, CHOH), 4.48* (m, 1H, NCHCH3 ), 4.50* (m, 1H, NCHCH3 ), 2.92* (m, 1H, H2), 2.88* (s, 3H, NCH 3 ), 2.82 (s, 3H, NCH 3 ), 2.78 (m, 1H, H2), 2.68 (m, 1H, one of H9), 2.55 (m, 1H, one of H9), 2.38 (m, 1H, H7), 2.21 (br, s, OH), 1.80 (m, 1H, H4), 1.58* (m, 1H, H4), 1.46 (m, 1H, one of H3), 1.38 (m, 1H, one of H3), 1.23 (m, 2H, H6), 1.05 (m, 9H, H1, CH3 CHN, H8), 0.98* (d, 3H, J = 6.6 Hz, H1), 0.82* (m, 6H, CH 3 CHN, H8), 0.77 (d, 3H, J = 6.6 Hz, H5). 13 C NMR (100 MHz, CDCI~ o: (3:1 rotamer ratio, * denotes minor rotamer peaks) 179.1, 177.9*, 142.5, 141.4*, 141.1, 129.4*, 129.1, 128.6*, 128.2, 128.0, 127.4, 126.8*' 126.3, 125.6; 76.4, 75.2*, 57.9, 44.7*, 44.4, 41.9, 41.6*, 34.0, 33.0*, 32.4, 32.0, 27.9, 27.6*, 26.9*, 19.3, 19.2, 17.6*, 17.1, 15.4*, 14.3. FTIR (neat, cm-1): 3383 (br, m, OH), 1618 (s, C=O). Analysis: Calcd for C26H 37N0 2 : C, 78.94; H, 9.43, N, 3.54. Found: C, 78.74; H, 9.16; N, 3.47. 1LC (30% EtOAc-hexanes), R; 33: 0.13 (UV, PMA). 69: 0.66 (UV, PMA). 101 ~ 9H30 ~~CH3 N :: LOA, LiCI; <?H3 0 ~ I OH CH3 ent-1 ~ THF, 23 oc 3 6 9 = Jl2~4~7~ ~, ~ ~ j ( -~ 0 H CH3 CH3 CH3 CH3 1 5 8 34 94% [1R(2S.4S.6S).2RJ-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N.2.4.6-tetramethyl Benzeneheptanamide 3 4 A solution of n-butyllithium in hexanes (2.33 M, 5.55 mL, 12.9 mmol, 3.86 equiv) was added via cannula to a suspension of lithium chloride (1.77 g, 41.7 mmol, 12.5 equiv) and diisopropylamine (2.04 mL, 14.6 mmol, 4.36 equiv) in tetrahydrofuran (9 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of ent-1 (1.48 g, 6.70 mmol, 2.00 equiv) in tetrahydrofuran (24 mL, followed by a 5-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 CC for 40 min, at 0 OC for 10 min, and at 23 °C for 3 minutes, whereupon a solution of the iodide 69 (1.01 g, 3.35 mmol, 1 equiv) in tetrahydrofuran (3 mL, followed by a 2-mL rinse) was added. The mixture was stirred at 23 OC for 18 h then was quenched by the addition of75% saturated aqueous ammonium chloride solution (40 mL). Organic solvents were removed in vacuo, and the resulting aqueous solution was extracted with ethyl acetate (3 x 25 mL). The combined organic fractions were washed with brine (7 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (40% ethyl acetate-hexanes) furnished amide 34 as a viscous oil (1.25 g, 94%). Chiral capillary GC analysis43 of the corresponding acetate ester, prepared as described above for amide 28, established that the ratio of the (2S,4S,6S) diastereomer to the (2S,4S,6S) diastereomer was 199:1. 102 1 H NMR (400 MHz, CDC13) 8: (3:1 rotamer ratio, * denotes minor rotamer peaks) 7.0--7.4 (m, lOH, aromatic), 4.60 (m, 1H, CHOH), 4.57* (m, 1H, CHOH), 4.40* (m, 1H, NCHCH 3), 4.09* (m, 1H, NCHCH3 ), 3.01 * (m, 1H, H2), 2.90* (s, 3H, NCH 3 ), 2.84 (s, 3H, NCH 3), 2.69 (sx, 1H, J = 6.6 Hz, H2), 2.59 (dd, 1H, J 1 = 13.2 Hz, J2 = 5.9 Hz, one of H9), 2.35 (dd, 1H, J 1 = 13.2 Hz, J 2 = 8.6 Hz, one of H9), 1.85 (m, 2H, H7, H4), 1.65 (m, 2H, H3), 1.52 (m, 2H, H6), 1.12 (d, 3H, J = 6.6 Hz, H1), 1.09* (d, 3H, H1), 1.06 (d, 3H, J = 6.6 Hz, H8), 0.99* (d, 3H, J = 7.0 Hz, H8), 0.87* (d, 3H, J = 6.6 Hz, H5), 0.82 (d, 3H, J = 6.6 Hz, H5), 0.73 (d, 3H, J = 6.2 Hz, CH 3CHN). 13 C NMR (1 00 MHz, CDCl~ 3: (3:1 rotamer ratio, * denotes minor rotamer peaks) 178.4, 177.3*, 142.4, 141.7*, 141.3*, 141.1, 128.9, 128.2*, 127.9, 127.8, 127.1, 126.7*, 126.1, 125.3, 75.9, 74.9*, 57.9, 57.6*, 44.2, 44.1, 41.9, 33.7, 32.8*, 32.5, 32.0, 27.7, 26.9*, 19.8*, 19.4, 19.0, 18.2*, 17.6, 15.3*, 14.1. FTIR (neat, cm-1): 3384 (br, m, OH), 1620 (s, C=O). HRMS (FAB): Calcd for C26H 38 N0 2 (MHt: 396.2903. Found: 396.2894. TLC (30% EtOAc-hexanes), R; 34: 0.16 (UV, PMA). 69: 0.66 (UV, PMA). 103 Oyt~~OH OH CH3 10 LOA, LiCI;C6 H5 CH 2 Br THF, 0 oc 84% flS(R) .2S)-a-Hydroxy-N-(2hydroxy-1-methy1-2-phenylethy12-N-methyl Benzene- propionaroide 3 5 A solution of n-butyllithium in hexanes (2.36 M, 1.20 mL, 2.83 mmol, 6.05 equiv) was added to a suspension of lithium chloride (262 mg, 6.18 mmol, 13.2 equiv) and diisopropylamine (0.433 mL, 3.09 mmol, 6.60 equiv) in tetrahydrofuran (3 mL) at-78 °C. The suspension was warmed briefly to 0 OC then was cooled to -78 °C. A solution of amide 10 (230 mg, 1.03 mmol, 2.20 equiv) in tetrahydrofuran (2 mL, followed by a 1-mL rinse) was added dropwise via cannula. The reaction mixture was stirred at -78 OC for 30 min, at 0 OC for 10 min, then was cooled to -78 °C. Benzyl bromide (56.0 J.LL, 0.468 mmol, 1 equiv) was added, and the mixture was warmed to 0 °C. The mixture was stirred at 0 OC for 4 h then was quenched by the sequential addition of half-saturated aqueous ammonium chloride solution (5 mL) and half-saturated brine (5 mL). The mixture was extracted with ethyl acetate (3 x 20 mL), and the combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (72% ethyl acetate-hexanes) afforded amide 35 as a viscous oil (124 mg, 84%). Analysis by 1H NMR spectroscopy (300 MHz, C6D6) established that amide 3 5 was of 82% de. 104 1 H NMR (300 MHz, C 6DJ 8: 7.0-7.6 (m, 10 H, aromatic), 4.65 (br, s, 2H, OH), 4.55 (m, 1H, NCHCH3 ), 4.44* (m, 1H, COCH), 4.38 (m, 1H, COCH), 4.24 (m, 1H, PhCHOH), 3.98* (m, 1H, PhCHOH), 3.84* (m, 1H, CHNCH 3), 3.53* (m, 1H, one of PhCH 2 ), 3.10* (m, 1H, one of PhCH 2 ), 2.84 (s, 1H, one of PhCH 2 ), 2.82 (s, 1H, one of PhCH2 ), 2.81 * (s, 3H, NCH 3), 2.16 (s, 3H, NCH 3 ), 0.63 (d, 3H, J = 6.9 Hz, CH 3CHN), 0.41 * (d, 3H, J = 6.7 Hz, CH 3 CHN). FI1R (neat, cm-1): 3382 (br, s, OH), 3029 (w), 1627 (s, C=O), 1495 (m), 1455 (m), 1392 (m), 1079 (m), 1052 (m), 753 (m), 701 (s) HRMS(FAB): Calcd for C 19H 24N0 3 (MHt: 314.1756. Found: 314.1761. 35: 0.41 (UV, PMA). 10: 0.31 (UV, PMA). 105 H3 N"'H crotonyl chloride, Et3 N 1 CH 2 C~,oac OH CH3 H3 0 N~CH3 I OH 54% CH3 36 CS. S)-N-(2-Hydroxy-1-methyl-2-phenylethyl)-N-methyl Crotonamide 3 6 An ice-cooled solution of crotonyl chloride (14.5 g, 138 mmol, 1 equiv) in dichloromethane (70 mL) was added via cannula over 5 min to a solution of pseudoephedrine (23.5 g, 142 mmol, 1 equiv) and triethylamine (25.7 mL, 185 mmol, 1.30 equiv) in dichloromethane (300 mL) at 0 °C. The reaction mixture was stirred at 0 'C for 10 min then excess acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL). .The mixture was partitioned between dichloromethane (300 mL) and saturated aqueous sodium bicarbonate solution (40 mL). The organic layer was separated and extracted sequentially with saturated aqueous sodium bicarbonate solution (2 x 40 mL) and 3 N aqueous hydrochloric acid solution (3 x 40 mL). The organic layer was dried over sodium sulfate and was concentrated. Recrystallization of the crude product from hot toluene (110 °C, 70 mL) afforded amide 36 as a yellow crystalline solid (18.5 g, 54% yield): mp 91-93 °C. 106 (4:1 rotamer ratio, * denotes minor rotamer peaks) 7.2-7.4 (m, 5H, aromatic), 6.85-7.00 (m, 1H, CH3 CH=CH), 6.37* (d, 1H, J = 15.1 Hz, CH3 CH=CH), 6.20 (d, 1H, J = 14.4 Hz, CH3 CH=CH), 4.59 (d, 1H, J = 8.2 Hz, CHOH), 4.47 (m, 1H, NCHCH 3), 4.15 (br, 1H, OH), 2.94* (s, 3H, NCH 3), 2.87 (s, 3H, NCH 3), 1.89 (dd, 3H, J 1 = 6.8 Hz, J 2 = 1.5 Hz, CH 3 CH=CH), 1.10 (d, 3H, J = 6.9 Hz, CH 3CHN), 0.98* (d, 3H, J = 6.8 Hz, CH 3CHN). FTIR (neat, cm-1): 3368 (br, m, OH), 1659 (s), 1596 (s), 1452 (m), 1406 (m), 1050 (m), 762 (m), 703 (m). HRMS (FAB): Calcd for C 14H20 N0 2 (MHt: 234.1494. Found: 234.1503. 36: 0.57 (UV, PMA). pseudoephedline: 0.05 (UV, PMA). 107 H3 0 N~CHs I OH CH 3 36 LiTMP, LiCI;C 6 H 5 CH 2 Br THF, -78 oc 72"/o Benzene- f1S(S).2Sl-a-Yinyl-N -(2-hydroxy-1-methyl-2-phenylethyl)-N-methyl propionamide 3 7 A solution of n-butyllithium in hexanes (2.25 M, 1.02 mL, 2.30 mmol, 2.30 equiv) was added to a suspension of lithium chloride (254 mg, 6.00 mmol, 6.00 equiv) and 2,2,6,6-tetramethylpiperidine (0.422 mL, 2.50 mmol, 2.50 equiv) in tetrahydrofuran (3 mL) at-78 °C. The suspension was stirred at-78 °C for 5 minutes then was warmed to 0 oc and held at that temperature for 20 minutes. An ice-cooled solution of amide 36 (233 mg, 1.00 mmol, 1 equiv) in tetrahydrofuran (2.5 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was cooled to -78 CC and maintained at that temperature for 10 minutes, whereupon benzyl bromide (0.420 mL, 3.50 mmol, 3.50 equiv) was added dropwise via syringe. The mixture was stirred at -78 CC for 5 h, then was treated with a solution of acetic acid and ether (50% v/v, 2 mL). The mixture was · warmed to 23 CC and was partitioned between half-saturated aqueous sodium bicarbonate solution (75 mL) and ethyl acetate (15 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 15 mL). The combined organic fractions were washed with brine (5 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (35---+ 55%) afforded amide 37 as a white crystalline solid (232 mg, 72%). 1 H NMR analysis (300 MHz, C 6D 6) and chiral capillary GC analysis43 of the corresponding trimethylsilyl ether, prepared as described above for amide 11, established that amide 3 6 was of93% de. Recrystallization of the solid (1.0 g, obtained from the combined yields of several of the above-mentioned reactions) from hot ethyl acetate (70 °C, 10 mL) afforded 108 white crystals (520 mg, 52% recovery, 36% overall yield). Chiral capillary GC analysis, as described above, established that amide 37 was of;:::99% de: mp 114-116 °C. 1 H NMR (300 MHz, CDClJ, S: (3:1 rotamer ratio, * denotes minor rotamer peaks) 7.15-7.40 (m, 10H, aromatic), 5.87 (m, 1H, CH=CH2), 5.04 (m, 2H, CH=CH2 ), 4.55 (dd, 1H, 1 1 = 7.6 Hz, 12 = 6.7 Hz, CHOH), 4.45 (dd, 1H, 1 1= 8.6 Hz, 12 = 2.5 Hz, CHOH), 4.38 (br, 1H, NCHCH3 ), 3.76* (m, 1H, CHCH2 Ph), 3.48 (m, 1H, CHCH2Ph), 3.17 (m, 2H, one of PhCH 2), 2.87* (s, 3H, NCH 3 ), 2.80 (m, 2H, one of PhCH2 ), 2.69 (s, 3H, NCH 3), 0.99 (d, 3H, 1 = 6.9 Hz, CH 3), 0.93* (d, 3H, 1 = 6.8 Hz, CH 3 ). FTIR (neat, cm-1): 3378 (br, m, OH), 3027 (m), 2977 (m), 1618 (s, C=O), 1493 (m), 1453 (m), 1406 (m), 1115 (m), 1049 (m), 919 (m), 752 (m), 700 (s). HRMS (FAB): Calcd for C 21 ~ 6N0 2 (MHt: 324.1964. Found: 324.1960. 1LC (80% EtOAc-hexanes), Rf 37: 0.57 (UV, PMA). 36: 0.30 (UV, PMA). 109 He Me~M N /} ea .LiO~)-Hb . Ha 0 N,Jl_..CHa __L_D_A_ _ I OH CHa 1 THF -78--+ 23 Ph ~c~ oc OLt Ha structure X structure Y Pseudoephedrine Propionamide Enolate A solution of n-butyllithium in hexanes (2.42 M, 0.860 mL, 2.08 mmol, 2.08 equiv) was added to a solution of diisopropylamine (0.320 mmol, 2.28 mmol, 2.28 equiv) in tetrahydrofuran (2.5 mL) at-78 °C. The solution was wa1med briefly to 0 °C, then was cooled to -78 °C. An ice-cooled solution of amide 1 (221 mg, 1.00 mmol, 1 equiv) in tetrahydrofuran (2.5 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stirred at -78 °C for 1 h, at 0 OC for 11 min, and at 23 OC for 3 min. An aliquot from the reaction mixture (700 J.!L) was withdrawn by microliter syringe and was transferred to a 5-mL flask. Volatile solvents were removed under vacuum (0.5 mm Hg for 1 h). The residue was dissolved in d8-tetrahydrofuran (700 J.!L), and the solvent was removed under vacuum (0.5 mm Hg for 10 min). The residue was dissolved in d8tetrahydrofuran (700 11L) and the solution was transferred to an NMR tube. 110 H NMR (300 MHz, THF-d8) o: 1 (1:1 mixtureofstructure X and structure Y) 6.9-7.8 (m, 5H, aromatic), 4.83 (s, 0.5H, Hb of Y), 4.56 (d, 0.5H, J = 8.0 Hz, Hb of X), 3.58 (obscured by THF-d8 , m, 0.5H, CHNCH 3 of X), 3.34 (qt, 0.5H, J = 6.3 Hz, He of X), 3.19 (qt, 0.5H, J = 6.4 Hz, He of Y), 2.97 (m, 0.5H, CHNCH 3 of Y), 2.82 {residual HN[CH(CH 3) 2] 2 }, 2.52 (s, 1.5H, NCH 3 of X), 1.82 (s, 1.5H, NCH 3 of Y), 1.73 (obscured by THF-d8 , 1.5H, CH 3 CHN of Y), 1.43 (d, 1.5H, J =6.3 Hz, CH3C=C0Li of X), 1.28 (d, 1.5H, J = 6.4 Hz, CH3C=C0Li of Y), 0.93 {residual HN[CH(CH 3 ) 2] 2 }, 0.60 (d, 1.5H, J = 7.2 Hz, CH 3CHN of X). 11 1 Chapter 2 Hydrolysis of Pseudoephedrine Amides to Form Highly Enantiomerically Enriched Carboxylic Acids 112 Introduction The diastereoselective alkylation of pseudoephed1ine amide enolates does not in and of itself constitute a valuable addition to synthetic methodology unless the alkylation products can be transformed into useful materials. For this reason, much effort has focused on the development of methods to transfmm the alkylated amides of Tables 3 and 4 into useful products. Conditions were developed to transform these alk:ylated pseudoephedrine amides directly into chiral carboxylic acids, alcohols, aldehydes, and ketones44 of high enantiomedc excess (ee). 45 Of these, the most challenging transfmmation was the simple hydrolysis reaction, for which basic and acidic conditions have been developed. The choice of a hydrolysis method will be dictated by the substrate and then by consideration of cost and convenience, as outlined below. Basic Hydrolysis of Alkylated Pseudoephedrine Amides to Form Carboxylic Acids Conditions for the base-promoted hydrolysis of pseudoephedrine amides"b.c were developed in conjunction with a protocol for the acid-promoted hydrolysis of pseudoephedrine amides (vide infra). 44 The procedure was optimized for the highly epimedzable phenylacetamide substrate 20, 44 and the use of 5 equiv of tetra-nbutylammonium hydroxide in a mixture of water and tert-butyl alcohol (4:1, respectively) at reflux proved to be optimal with respect to reaction time, yield, and product ee. When these conditions were employed for the basic hydrolysis of other alkylated pseudoephedrine amides, results were generally far superior to those observed with the epimedzable substrate 20 (Table 6). A convenient work-up procedure for these hydrolyses involved acidification with 3 N aqueous hydrochlmic acid solution followed by extraction of the product into ether. Tetra-n-butylammonium salts were then readily removed by washing the ethereal product solution with water. Where the expense of tetra- 113 Table 6. Basic Hydrolysis of Pseudoephedrine Amides 5 equiv n-Bu 4 NOH 1:4 t-BuOH : H 2 0, reflux entry substratea product 1 isol yield (%) isol ee or de(%) 93 94 93 97 92 69 91 94 89 82 88 93 90 84 82 64 86 95 84 95 39 0 0 2 jl__cH3 Xy+ ' CH2(Cf+.!)2CH3 HO~CH3 CH2(CH2)2CH3 40 12 0 3 0 jl__cH3 Xv+ ~ CH 2 0C~C 6 H 5 HO ~CH3 ; CH 20CH 2C 6H 5 41 13 0 4 0 jl__cH2C6Hs Xv+ ; CH3 HO ~CH2C6Hs ; CH3 16 42 0 ~CH 2 C 6 H 5 5 HO , CH2(CH2) 2CH3 43 0 6 0 jl__cH 2(CH 2)2CH 3 X,+ i CH3 HO ~CH 2 (CH 2)2CH 3 i CH3 18 44 0 7 HOYyCH2(CH2)2CH3 CH2C6Hs 45 ~ 8 HO 20 46 0 9 X,~CH3 CH CH 3 3 0 HO~CH 3 CH 3 CH 3 27 47 0 10 , CH~H3 x~CH3 0 HO ~ , , CH3 CH3 CH3 CH3 CH3 28 48 Substrates 11, 12, 19, and 20 were of ~99% de. Substrates 13, 17, ~md 28 were of 98% de, substrates 16 and 27 were of 97% de, and substrate 18 was of 96% de. a 114 n-butylammonium hydroxide is a consideration, or in cases where the product carboxylic acid is poorly soluble in ether (making removal of tetra-n-butylammonium salts difficult), a second alkaline hydrolysis procedure was developed employing sodium hydroxide (5-8 equiv) as the base in a 2:1:1 mixture of water, methanol, and tert-butyl alcohol at reflux. This is an excellent alternative method and was employed, for example, for the hydrolysis of the 2-methyl succinic acid derivative 15 (74% yield, 94% ee), where the poor ether solubility of the product, 2-methyl succinic acid, precluded the use of tetra-n- 0 HO~OH CH3 0 49 74% yield, 94% ee butylammonium hydroxide as base. For other substrates, this altemative hydrolysis procedure affords products of slightly lower ee as compared to the method employing tetra-n-butylammonium hydroxide as base. For example, hydrolysis of substrate 11 with sodium hydroxide in a 2:1: 1 mixture of water, methanol and tert-butyl alcohol affords the corresponding acid 39 in 98% yield and 92% ee 44 whereas hydrolysis of 11 with tetra-nbutylammonium hydroxide affords acid 39 in 93% yield and 94% ee (entry 1, Table 6). Although the base-promoted hydrolysis of pseudoephedrine amides typically affords products in lower ee than does the acid-promoted hydrolysis, these procedures offer viable alternatives for the hydrolysis of acid-sensitive substrates. Though a substantial degradation in ee occurs for certain substrates (e.g., substrates 13, 17, 19, and 20, Table 6), in at least one case (entry 10, Table 6), basic hydrolysis proceeds with less epimerization than the acidic hydrolysis method (95% de versus 93% de, respectively). 115 The mechanism of both of the base-promoted hydrolysis reactions is believed to involve initial rate-limiting intramolecular N ------+ 0 acyl transfer followed by rapid saponification of the resulting ~-amino ester intermediate. As in the acidic hydrolysis protocol, the pseudoephedrine auxiliary may be recovered in high yield from basic hydrolyses, if desired, by a simple extractive isolation procedure. Acidic Hydrolysis of Alkylated Pseudoephedrine Amides to Form Carboxylic Acids For alkylation products that are not acid-sensitive, hydrolysis 11 b,c to the corresponding carboxylic acid can generally be effected in excellent chemical yield. 8'44 When the pseudoephedrine amide substrate is heated at reflux in a 1: 1 mixture. of sulfuric acid (9-18 N) and dioxane, the substrate initially undergoes a rapid intramolecular N ------+ 0 acyl transfer reaction followed by rate-limiting hydrolysis of the resulting ammonium ester intermediate to the carboxylic acid (Figure 6). Although this protocol typically affords reflux reflux Figure 6. Sulfuric acid-promoted hydrolysis of pseudoephedrine amides. 116 carboxylic acids with virtually complete preservation of stereochemical integrity, in one case (acid 48), prolonged exposure to the reaction conditions has been found lower the de of the product acid (Scheme VITI). Scheme VIII ~ Jly /". .y /". . 1 :1 18 N H2S0 4 :dioxane CH3 CH3 CH3 reflux , 2 h 9H 3 ~t;r OH -cH3 27 47: 80% yield, 95% de ~ <?H3 0 ~ ~ . NI . . CH3 OH CH3 CH 3 CH3 1:118N H2 S0 4 :dioxane reflux, 2 h 28 ~ 48: 74% yield, 93% de <?H3 0 ~ ~ . OH - NI . . CH3 CH3 CH3 CH3 1:118N H 2 S0 4 : dioxane reflux, 3 h 28 48: 77% yield, 77% de Hydrolysis of Pseudoephedrine Amides Involving In Situ Borane-Amine Complexation One of the problematic substrates for both the basic and acidic hydrolyses was the a-benzyloxymethyl-substituted substrate 13. Basic hydrolysis (tetra-n-butylammonium hydroxide, water-tert-butyl alcohol, reflux) of amide 13 resulted in a 92% yield of the corresponding acid, but the ee was only 64%. Acidic hydrolysis (18 N sulfuric acid, dioxane, reflux) resulted in the complete decomposition of amide 13. 8a 117 It was known for the acidic hydrolysis of alk:ylated pseudoephedrine amides that the reaction proceeds via rapid N ~ 0 acyl transfer (forming a hydrosulfate ester) followed by rate-limiting hydrolysis (Figure 6, above). Although amide 13 decomposes in a 1:1 mixture of 18 N sulfuric acid and dioxane at reflux, it undergoes clean N ~ 0 acyl transfer at 23 OC in 2-5 hours under otherwise identical reaction conditions to furnish the corresponding hydrosulfate salt in approximately 95% de. Though water-soluble, this hydro sulfate salt can be salted out of the aqueous phase with sodium chloride and extracted with ethyl acetate. Attempts to hydrolyze the hydrosulfate salt under basic conditions (sodium hydroxide or tetra-n-butylammonium hydroxide, 23 °C) resulted primarily instead in reversion to amide 13. Attempts to protect the nitrogen as the corresponding trifluoroacetamide, acetamide, or priopionamide (to prevent 0 ~ N acyl transfer), followed by alkaline hydrolysis of the ester functionality, gave only fair yields of the desired acid. Competitive hydrolysis of the amide functionality, followed by reversion to amide 13 also occurred. Though ester functionalities are typically more susceptible to hydrolysis than amide functionalities, the rate of hydrolysis of the ester functionality was probably retarded due to increased steric hindrance. We therefore required a nitrogen protecting group that would be stable to alkaline conditions. While N-tert-butyloxycarbonyl (N-BOC) carbamates are stable to basic conditions, the BOC group was deemed undesirable because it costs more per mole than does pseudoephedrine itself. The key to achieving hydrolysis involved the formation of a stable amine-borane complex in situ by the addition of lithium borohydride to the N ~ 0 acyl transfer intermediate (Scheme IX). The sequence of N ~ 0 acyl transfer, amine-borane complex formation, and saponification was thus accomplished as follows. A solution of the 118 Scheme IX LiB~ pseudoephedrine amide substrate in THF was stirred in a 1:1 mixture of 18 N H 2 S0 4 and dioxane for 2-5 h at 23 °C to furnish the N ---+ 0 acyl transfer hydrosulfate salt. After an extractive work-up, deprotonation of the hydrosulfate salt with lithium borohyddde (2.0 M in THF, 1.2 equiv) in THF at 23 OC afforded an amine-borane complex which did not undergo reduction. After another extractive work-up, subjection of the amine-borane complex to aqueous tetra-n-butylammonium hydroxide (5 equiv) at 23 OC effected ester hydrolysis to liberate the desired carboxylate product. Application of this methodology to the hydrolysis of the a-benzyloxymethylsubstituted-amide 13 afforded acid 41 in 80% yield and 88% ee, and hydrolysis of the benzylated pseudoephedrine propionamide (11) afforded acid 39 in 79% yield and >99% ee (Scheme X). 44 Although labor-intensive, this method afforded acid 39 in higher ee (99%) than the one-step hydrolysis protocols discussed above. For instance, the use of H 2 S04 in dioxane afforded acid 39 in 97% ee, n-Bu4 NOH in water and tert-butyl alcohol afforded 39 in 94% ee, and NaOH in water-tert-butyl alcohol-methanol afforded 39 in 92% ee. This general procedure (N---+ 0 acyl transfer, amine-borane complex formation, 119 Scheme X 0 HO~CH 3 3) n-BL4NOH CH20CH2 C5Hs 41: 80% yield, 88% ee 0 HO~CHa CH2C5Hs 39: 79% yield, >99% ee and saponification) has been subsequently modified so that it can be canied out as a onepot procedure. 8b' 44 120 Experimental Section General Procedures. All non-aqueous reactions were performed in flame-dried round-bottomed or modified Schlenk (Kjeldahl shape) flasks, equipped with a magnetic stirring bar and fitted with a rubber septum under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe unless otherwise noted. Organic solutions were concentrated by rotary evaporation at -25 Torr. Analytical thin-layer chromatography was performed using glass plates precoated with 0.25-mm 230---400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran was distilled under nitrogen from sodium benzophenone ketyl. Dichloromethane and triethylamine were distilled under nitrogen from calcium hydride. Instrumentation. Infrared data are presented as follows: frequency of absorption (cm-1), intensity of absorption (br =broad, s = strong, m =medium). 1H NMR spectra were recorded at 400 or 300 MHz, and 13 C NMR spectra were recorded at 100 or 75 MHz; chemical shifts are expressed in parts per million (8 scale) downfield from tetramethylsilane. 1 H NMR chemical shifts are referenced to the signal for residual hydrogen in the NMR solvent (CHC13 : 8 7.26, C 6HD 5 : 8 7.15) or to tetramethylsilane. Data are presented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, m = multiplet), integration, and coupling constant in Hertz. 13 C NMR chemical shifts are referenced to the carbon signal for the solvent (CDC13 : 8 77.0, C 6D 6 : 8 128.0). Mass spectrometry was performed at the California Institute of Technology or at the University of California at Irvine. Combustion analyses were performed by Quantitative Technologies Incorporated. 121 Chiral capillary gas chromatography (GC) analysis was carried out using an Alltech Chirasil-Val chiral fused silica capillary column, under isothermal conditions, with a column head pressure of 17 psi. 122 Oyr~JyCH 3 0 H CH 3 CH 2 CsHs 0 5 equiv n-Bu4NOH ~CH3 : HO 1:4 t-BuOH : H2 0, reflux 11 93"/o CH 2 C 6 H 5 39 (R)-a-Methyl Benzeneyropionic Acid 3 9 A 100-mL round-bottomed :flask equipped with a reflux condenser was charged with amide 11 (500 mg, 1.61 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 5.21 g, 8.03 mmol, 5.00 equiv), tert-butyl alcohol (5 mL), and water (15 mL) and the biphasic mixture was heated at reflux for 24 h. The mixture was cooled to 23 °C, then was partitioned between 0.5 N aqueous sodium hydroxide solution (200 mL) and ether (25 mL). The aqueous layer was separated and extracted with two 25-mL portions of ether, then was brought to pH~ 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with three 35-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 39 as a clear liquid (245 mg, 93%). Coupling of acid 39 (25 mg, 0.15 mmol, 1 equiv) with (R)a-methylbenzylamine (24 J.lL, 0.19 mmol, 1.2 equiv) in the presence of 1-(3dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (44 mg, 0.23 mmol, 1.5 equiv), 1-hydroxybenzotriazole hydrate (31 mg, 0.23 mmol, 1.5 equiv), and triethylamine (86 I-LL, 0.62 mmol, 4.0 equiv) in N,N-dimethylformamide (0.5 mL) at 23 CC for 20 h gave the corresponding (R)-a-methylbenzyl amide46 which was analyzed by chiral capillary GC to establish an ee of94% for acid 39. The purity of acid 39 was estimated to be ~95% by 1H and 13C NMR spectroscopic data. 123 7.25 (m, 5H, aromatic), 3.09 (dd, 1H, 11 = 13.1 Hz, 12 = 6.1 Hz, one of PhCH2 ), 2.75 (m, 2H, one of PhCH 2 , CH3 CH), 1.18 (d, 3H, J = 6.8 Hz, CH 3 ). C NMR (7 5 MHz, CDCl~ 8: 13 182.5, 139.0, 129.0, 128.4, 126.4, 41.2, 39.3, 16.5. FTIR (neat, cm-1): 297 6 (br, s, OH), 1707 (s, C=O). HRMS (FAB): Calcd for C 10H 120 2 (Mt: 164.0838. Found: 164.0832. 39: 0.29-0.51 streak (UV, PMA). 11: 0.65 (UV, PMA). 124 Hs~CHs NI . : 0 H CH 3 CH 2 (CH 2 )2CH 3 12 0 5 equiv n-Bu4NOH ~CHs : HO 1:4 t-BuOH : H2 0, reflux CH 2 (CH 2 )2CH 3 40 CR)-2-Methyl Hexanoic Acid 4 0 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 12 (80.0 mg, 0.288 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 0.930 g, 1.44 mmol, 5.00 equiv), tert-butyl alcohol (1 mL), and water (3.1 mL) and the biphasic mixture was heated at reflux for 22 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (100 mL) and ether (10 mL). The aqueous layer was separated and extracted with two 10-mL portions of ether, then was brought to pH~ 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chlmide and was extracted with three 15-mL portions of ether. The combined ether extracts were washed with water (5 mL), then were dried over sodium sulfate and were concentrated to afford acid 40 as a clear liquid (35 mg, 93%). Chiral capillary GC analysis of the corresponding (R)-amethylbenzyl amide, 46 prepared as described above for acid 39, established that acid 4 0 was of 97% ee. The purity of acid 40 was estimated to be ;:::95% by 1H and 13 C NMR spectroscopic data. 125 2.44 (sx, 1H, J = 6.9 Hz, COCH), 1.70 (m, 1H, one of COCHCH 2 ), 1.45 (m, 1H, one of COCHCH2), 1.35 (m, 4H, CH 3CH 2CH 2), 1.17 (d, 3H, J = 7.0 Hz, CH3CHCOOH), 0.90 (m, 3H, CH 3 ). 13 C NMR (75 MHz, CDC1 3) o: 183.9, 39.4, 33.2, 29.3, 22.6, 16.8, 13.9. FI1R (neat, cm-1): 3028 (br, s, OH), 1712 (s, C=O). LRMS (EI): mlz (relative intensity) 101 (5), 87 (28), 74 (100), 55 (11). TLC (80% EtOAc-hexanes), R; 40: 0.61 (UV, PMA). 126 5 equiv n-Bu4 NOH 1 :4 t-BuOH : H20, reflux 0 ~CH 3 HO : CH 20CH2C5Hs 41 (R)-3-Benzyloxy-2-methylpropionic Acid 41 A 25-mL round-bottomed flask equipped with a reflux condenser was charged with amide 13 (0.262 g, 0.767 mmol, 1 equiv), aqueous teu·a-n-butylammonium hydroxide solution (40% w/w, 2.49 g, 3.83 mmol, 5.00 equiv), tert-butyl alcohol (2.7 mL), and water (8 mL) and the biphasic mixture was heated at reflux for 26 h. The mixture was cooled to 23 °C, then was partitioned between 1.5 N aqueous sodium hydroxide solution (100 mL) and ether (20 mL). The aqueous layer was separated and extracted with two 20mL portions of ether, then was brought to pH ~ 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with three 35-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 41 as a clear liquid (138 mg, 92%). Chiral capillary GC analysis of the corresponding (R)-a-methylbenzyl amide, 46 prepared as described above for acid 39, established that acid 41 was of 69% ee. The pmity of acid 41 was estimated to be ~95% by 1H and 13C NMR spectroscopic data. 127 8.8-9.2 (br, 1H, HOOC), 7.25-7.37 (m, 5H, aromatic), 4.55 (s, 2H, PhCH2 ), 3.66 (dd, 1H, 1 1 = 9.1 Hz, 12 = 7.4 Hz, one of CH3CHCH 2), 3.54 (dd, 1H, 1 1 = 9.1 Hz, 12 = 5.6 Hz, one of CH 3CHCH 2), 2.77-2.84 (m, 1H, CH 3CH), 1.22 (d, 3H, J = 7. 1 Hz, CH 3 ). C NMR (100 MHz, CDC13) o: 13 180.0, 137.9, 128.5, 127.8, 127.7, 73.3, 71.6, 40.1, 13.7. FTIR (neat, cm-1): 2800-3400 (br, s, OH), 1711 (s, C=O). HRMS (EI): Calcd for CuH 140 3 (Mt: 194.0943. Found: 194.0946. 41: 0.07-0.33 streak (UV, PMA). 13: 0.38 (UV, PMA). benzyl alcohol: 0.64 (UV, PMA). 128 1) H2S0 4 0 2) LiB~ HO.JiycH 3 3) n-Bu4NOH 80% CH2 0CH 2 CsHs 41 CRl-3-Benzyloxy-2-methylpropionic Acid 4 1 An ice-cooled solution of 18 N sulfuric acid (2.5 mL) was added to a solution of amide 13 (600 mg, 1.76 mmol, 1 equiv) in dioxane (2.5 mL) at 10 °C. The biphasic mixture was warmed to 23 OC and was held at that temperature for 3 h. The mixture was partitioned between brine (35 mL) and ethyl acetate (35 mL). The aqueous layer was separated and saturated with sodium chloride, then was extracted with ethyl acetate (3 x 35 mL). The combined organic fractions were d1ied over sodium sulfate and were concentrated to yield a fine white powder (610 mg). A pmtion (10.3% of recovered material, 64 mg) of the powder was dissolved in tetrahydrofuran (1 mL) and was cooled to 0 °C. A solution of lithium borohydride in tetrahydrofuran (2.0 M, 0.109 mL, 0.218 mmol, 1.20 equiv) was added slowly via sylinge, resulting in vigorous gas evolution. The mixture was stirred at 0 OC for 5 minutes, after which time bubbling had ceased, then excess hydride was quenched by the slow addition of 0.1 N aqueous hydrochloric acid solution (1 mL). The mixture was partitioned between 0.1 N aqueous hydrochloric acid solution (80 mL) and ethyl acetate (20 mL), and the aqueous layer was separated. The aqueous layer was extracted with ethyl acetate (2 x 20 mL), and the combined organic fractions were washed with brine (5 mL), then were dried over sodium sulfate and were concentrated. The residue was dissolved in tert-butyl alcohol (0.7 mL) and water (1 mL), and the biphasic mixture was cooled to 0 °C. An aqueous solution of tetra-n- butylammonium hydroxide (0.500 M, 1.80 mL, 0.905 mmol, 5.00 equiv) was added and the reaction mixture was warmed to 23 OC and held at that temperature for 10 h. The reaction mixture was partitioned between 1 N aqueous sodium hydroxide solution (100 129 mL) and ether (12 mL). The aqueous layer was separated and extracted with ether (2 x 12 mL). The aqueous layer was acidified to pH ::;; 2 by the careful addition of 3 N aqueous hydrochloric acid solution, then was saturated with sodium chloride and was extracted with ether (3 x 30 mL). The combined organic fractions were washed with brine (5 rnL), then were dried over sodium sulfate and were concentrated to give the desired acid (28 rng, 80% from 1). Chiral capillary GC analysis of the corresponding (R)-a.-rnethylbenzyl arnide, 46 prepared as described above for acid 39, established that acid 41 was of 88% ee. Spectroscopic data were identical to those listed above. The purity of acid 41 was estimated to be ~95% by 1H and 13C NMR spectroscopic data. 53: 0.07-0.33 streak (UV, PMA). N ~ 0 acyl transfer: 0.13-0.26 streak (UV, PMA). 14: 0.38 (UV, PMA). 130 5 equiv n-Bu 4 NOH 0 1:4 t-BuOH : H20. reflux HO~ 91% 42 ~e llJ ($)-a-Methyl Benzenepropionic Acid 4 2 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 16 (77.0 mg, 0.248 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 0.803 g, 1.24 mmol, 5.00 equiv), tert-butyl alcohol (1 mL), and water (3.2 mL) and the biphasic mixture was heated at reflux for 22 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (100 mL) and ether (10 mL). The aqueous layer was separated and extracted with two 10-mL portions of ether, then was brought to pH :::;; 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with four 15-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 42 as a clear liquid (37 mg, 93% ). Chiral capillary GC analysis of the corresponding (R)-amethylbenzyl amide, 46 prepared as described above for acid 39, established that acid 42 was of 94% ee. The purity of acid 42 was estimated to be :2:95% by 1H and 13 C NMR spectroscopic data. Spectroscopic data were identical to those of its enantiomer, (R)-amethyl benzenepropionic acid (39). 42: 0.24-0.60 streak (UV, PMA). 16: 0.67 (UV, PMA). 131 ~ yH30 ~t;J~CH2Ph 0 H CH3 CH2(CH2)2CH3 5 equiv n-Bu 4 NOH 1 :4 t-BuOH : H2 0, reflux 17 0 ~CH2Ph HO 89"/o ~ CH2(CH2)2CH3 43 (S)-q-Butyl Benzenepropionic Acid 4 3 A 25-mL round-bottomed flask equipped with a reflux condenser was charged with amide 17 (275 mg, 0.778 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 2.52 g, 3.89 mmol, 5.00 equiv), tert-butyl alcohol (2.7 mL), and water (8 mL) and the biphasic mixture was heated at reflux for 24 h. The mixture was cooled to 23 °C, then was partitioned between I N aqueous sodium hydroxide solution (100 mL) and ether (20 mL). The aqueous layer was separated and extracted with two 20- mL portions of ether, then was brought to pH :::;; 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chl01ide and was extracted with three 35-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 43 as a clear liquid (143 mg, 89%). Chiral capillruy GC analysis of the corresponding (R)-a.-methylbenzyl amide, 46 prepared as desc1ibed above for acid 39, established that acid 43 was of 82% ee. The purity of acid 43 was estimated to be ~95% by 1H and 13C NMR spectroscopic data. 132 7.30 (m, 5H, aromatic), 2.98 (dd, 1H, 11 = 7.8 Hz, 12 = 13.5 Hz, one of PhCH 2 ), 2.70 (m, 2H, one of PhCH 2, HOOCCH), HOOCCHCH2), 1.55 1.65 (m, (m, 1H, 1H, one of one of HOOCCHCH 2), 1.30 (m, 4H, CH 3CH 2CH 2), 0.85 (m, 3H, CH 3). C NMR (75 MHz, CDC13) o: 13 181.8, 139.1, 128.9, 128.4, 126.4, 47.3, 38.1, 31.4, 29.3, 22.5, 13.9. FTIR (neat, cm-1): 3028 (br, s, OH), 1711 (s, C=O). HRMS (EI): Calcd for C 13H 18 0 2 (Mt: 206.1307. Found: 206.1314. 43: 0.30-0.57 streak (UV, PMA). 17: 0.61 (UV, PMA). 133 5 equiv n-Bu 4 NOH 1 :4 t-BuOH : H2 0, reflux 88% 0 HO~CHa CH 3 44 CS)-2-Methylhexanoic Acid 4 4 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 18 (80.0 mg, 0.288 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 0.930 g, 1.44 mmol, 5.00 equiv), tert-butyl alcohol (1 mL), and water (3.1 mL) and the biphasic mixture was heated at reflux for 23 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (100 mL) and ether (10 mL). The aqueous layer was separated and extracted with two 10-mL portions of ether, then was brought to pH::; 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chlmide and was extracted with three 15-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 44 as a clear liquid (33.0 mg, 88% ). Chiral capillary GC analysis of the corresponding (R)-a.- methylbenzyl amide, 46 prepared as described above for acid 3 9, established that acid 4 4 was of 93% ee. The purity of acid 44 was estimated to be ~95% by 1 H and 13 C NMR spectroscopic data. Spectroscopic data were identical to those of its enantiomer, (R)-2methylhexanoic acid (40). TLC (80% EtOAc-hexanes), R; 18: 0.56 (UV, PMA). 134 5 equiv n-Bu 4 NOH 1 :4 t-BuOH : H 20, reflux 90"/o 0 HO~CH3 CH2CsHs 45 (B)-a-Butyl Benzenepropionic Acid 4 5 A 50-mL round-bottomed flask equipped with a reflux condenser was charged with amide 19 (580 mg, 1.64 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 5.70 g, 8.79 mmol, 5.36 equiv), tert-butyl alcohol (5 mL), and water (14 mL) and the biphasic mixture was heated at reflux for 21 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (120 mL) and ether (25 mL). The aqueous layer was separated and extracted with two 25-mL po1tions of ether, then was brought to pH ::;; 1 by the addition of 6 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with three 35-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 45 as a clear liquid (305 mg, 90% ). Chiral capillary GC analysis of the corresponding (R)-amethylbenzyl amide, 46 prepared as described above for acid 3 9, established that acid 4 5 was of 84% ee. The purity of acid 45 was estimated to be 2::95% by 'H and 13 C NMR spectroscopic data. Spectroscopic data were identical to those of its enantiomer, (S)-abutyl benzenepropionic acid (43). 45: 0.58 (UV, PMA). 19: 0.75 (UV, PMA). 135 Hs;_{) NI - ::. 0 H CH3 CH 2 CHs 20 5 equiv n-Bu4NOH 1:4 t-BuOH : H2 0, reflux 82"/o (S)-a-Ethyl Benzeneacetic Acid 4 6 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 20 (86.0 mg, 0.276 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (40% w/w, 0.810 g, L25 mmol, 4.50 equiv), tert-butyl alcohol (1 mL), and water (3.2 mL) and the biphasic mixture was heated at reflux for 20 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (100 mL) and ether (10 mL). The aqueous layer was separated and extracted with two 10-mL portions of ether, then was brought to pH~ 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with three 15-mL portions of ether. The combined ether extracts were washed with water (10 mL), then were dried over sodium sulfate and were concentrated to afford acid 46 as a clear liquid (37.4 mg, 82%). Chiral capillary GC analysis of the corresponding (R)-amethylbenzyl amide, 46 prepared as described above for acid 39, established that acid 4 6 was of 64% ee. The purity of acid 46 was estimated to be ~95% by 1H and 13C NMR spectroscopic data. 136 7.25 (m, 5H, aromatic), 3.41 (t, 1H, J = 7.7 Hz, PhCH), 2.05 (m, 1H, one of CH 3 CH2 ), 1.76 (m, 1H, one of CH3CH2 ), 0.86 (t, 3H, 1 = 7.4 Hz, CH 3 ). 13 C NMR (7 5 MHz, CDCl:J 8: 180.5, 138.3, 128.6, 128.1, 127.4, 53.3, 26.3, 12.1. FTIR (neat, cm-1): 2967 (br, s, OH), 1712 (s, C=O). HRMS (EI): Calcd for C 10H 12 0 2 (Mt: 164.0837. Found: 164.0839. 46: 0.24-0.45 streak (UV, PMA). 20: 0.75 (UV, PMA). 137 H3 0 Jl 1';1' y ~ y 5 equiv n-Bu 4 NOH ..... -cH3 0 H CH3 CH3 CH3 1 :4 t-BuOH : H2 0, reflux Zl C2R.4S)-2.4-Dimethylhexanoic Acid 47 A 25-mL round-bottomed flask equipped with a reflux condenser was charged with amide 27 (197 mg, 0.674 mmol, 1 equiv), aqueous tetra-n.-butylammonium hydroxide solution (0.560 M, 6.00 mL, 3.37 mmol, 5.0 equiv), and tert-butyl alcohol (1.5 mL) and the biphasic mixture was heated at reflux for 24 h. The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (40 mL) and ether (5 mL). The aqueous layer was separated and extracted with three 5-mL portions of ether, then was brought to pH ~ 1 by the addition of 3 N aqueous hydrochloric acid solution. The acidified solution was saturated with sodium chloride and was extracted with three 20mL portions of ether. The combined ether extracts were washed with half-saturated brine (5 mL), then were dried over magnesium sulfate and were concentrated to afford acid 47 as a clear liquid (83.6 mg, 86%). The de of acid 47 was determined to be 95% by comparison of the 1H NMR spectrum with that of acid 48. estimated to be ~5% by 1H and 13C NMR spectroscopic data. The purity of acid 47 was 138 2.55 (m, 1H, H1), 1.55 (m, 1H, H4), 1.39 (m, 3H, H3, one ofH6), 1.17 (m, 1H, one of H6), 1.16 (d, 3H, J = 6.9 Hz, H2), 0.87 (m, 6H, H7, H5). 13 C NMR (7 5 MHz, CDCl:J 8: 184.1, 40.5, 37.3, 32.1, 29.5, 18.8, 16.9, 11.2. FTIR (neat, cm-1): 2800-3400 (br, m, OH), 1712 (s, C=O). HRMS (CI): Calcd for C8H 15 0 2Na2 Found: 189.0869. TLC (10% MeOH-C~Cl2), R; 47: 0.44 (PMA). 27: 0.57 (UV, PMA). (MN~-Ht: 189.0867. 139 H3 0 Jl--.../"'-... t;J' y y -cH3 1:1 18 N H 2 S0 4 : dioxane 0 H CH3 CH3 CH3 'Zl 0 reflux HoYTcH3 CH3 CH3 BJ'Io tfl (2R.4S)-2.4-Dimethylhexanoic Acid 4 7 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 27 (114 mg, 0.391 mmol, 1 equiv), dioxane (0.7 mL), and 18 N aqueous sulfuric acid (0.7 mL). The biphasic mixture was heated at reflux for 2.8 h, then was cooled to 23 °C. The pH of the mixture was adjusted to pH ~ 10 by the slow addition of 2 N aqueous sodium hydroxide solution (40 mL) and the resulting mixture was extracted with ether (3 x 7 mL). The aqueous phase was acidified to pH ::; 2 by the cautious addition of 3 N aqueous hydrochloric acid solution (40 mL). The acidified solution was saturated with sodium chloride and was extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over sodium sulfate and were concentrated to afford acid 47 as a clear liquid (45.0 mg, 80%). The de was determined to be 95% by comparison of the 1H NMR spectrum with that of acid 48. The purity of acid 47 was estimated to be ~5% by 1H and 13C NMR spectroscopic data. Spectroscopic and TLC data were identical to those listed above. 140 ~ 9H3 0 ~~ _ N CH3 ::: I ;:: ;: 0 H CH 3 CH 3 CHs 5 equiv n-Bu4 NOH 1:4 t-BuOH : H2 0, reflux 84% 28 0 1).3.67 HO~ .:. .:. CHs CH 3 CH3 2 5 48 C2S.4S)-2.4-Dimethylhexanoic Acid 4 8 A 25-mL round-bottomed flask equipped with a reflux condenser was charged with amide 28 (186 mg, 0_639 mmol, 1 equiv), aqueous tetra-n-butylammonium hydroxide solution (0_530 M, 6_00 mL, 3_2 mmol, 5_0 equiv), and tert-butyl alcohol (L5 mL) and the biphasic mixture was heated at reflux for 24 h_ The mixture was cooled to 23 °C, then was partitioned between 1 N aqueous sodium hydroxide solution (40 mL) and ether (5 mL)_ The aqueous layer was separated and extracted with three 5-mL portions of ether, then was brought to pH ~ 1 l;Jy the addition of 3 N aqueous hydrochloric acid solution_ The acidified solution was saturated with sodium chloride and was extracted with three 20mL portions of ether_ The combined ether extracts were washed with half-saturated brine (5 mL),. then were dried over magnesium sulfate and were concentrated to afford acid 48 as a clear liquid (77_9 mg, 84%)_ The de of acid 48 was determined to be 95% by comparison of the 1H NMR spectrum with that of acid 47_ estimated to be ~95% by 1H and 13C NMR spectroscopic data_ The purity of acid 48 was 141 1 HNMR (300_1\ffiz, CDCl) 8: 2.50-2.62 (m, 1H, H1), 1.68-1.78 (m, 1H, H4), 1.29-1.45 (m, 2H, H3), 1.18 (d, 3H, J = 7.0 Hz, H2), 1.08-1.15 (m, 2H, H6), 0.89 (d, 3H, J = 6.5 Hz, H5), 0.86 (t, 3H, J = 7.3 Hz, H6). 13 C NMR (7 5 MHz, CDCl~ 8: 183.8, 40.9, 37,5, 32.3, 29.5, 19.0, 17.9, 11.1. FTIR (neat,' cm-1): 3000-3400 (br, m, OH), 1708 (s, C=O). HRMs ccn: Calcd for C 8H 15 0 2N~ (MN~-Ht: 189.0867. Found: 189.0871. 48: 0.57 (PMA). 28: 0.72 (UV, PMA). 142 ~ <?H3 0 ~~ _ N . CH3 = = I 0 1:1 18 N H 2 S04 : dioxane = 0 H CH 3 CH 3 CH 3 28 reflux 74% H0 ~ : : CH3 CHa CHa 48 C2S.4S)-2.4-Dimethylhexanoic Acid 4 8 A 10-mL round-bottomed flask equipped with a reflux condenser was charged with amide 28 (109 mg, 0.375 mmol, 1 equiv), dioxane (0.6 mL), and 18 N aqueous sulfuric acid (0.6 mL). The biphasic mixture was heated at reflux for 2 h, then was cooled to 23 0 C. The pH of the mixture was adjusted to pH ::2: 10 by the slow addition of 2 N aqueous sodium hydroxide solution (40 mL) and the resulting mixture was extracted with ether (3 x 7 mL). The aqueous phase was acidified to pH ~ 2 by the cautious addition of 3 N aqueous hydrochloric acid solution (40 mL). The acidified solution was saturated with sodium chloride and was extracted with ethyl acetate (3 x 30 mL). The combined ethyl acetate extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over sodium sulfate and were concentrated to afford acid 48 as a clear liquid (39.8 mg, 74%). The de was determined to be 93% by comparison of the 1H NMR spectrum with that of acid 47. The purity of acid 48 was estimated to be ::2:95% by 1H and 13 C NMR spectroscopic data. Spectroscopic and TLC data were identical to those listed above. 143 NaOH t-BuOH, MeOH, H2 0, reflux 0 HO~OH CH 3 0 74% 49 (B)-a-Methyl Butanedioic Acid 4 9 A 25-mL round-bottomed flask equipped with a reflux condenser was charged with amide 15 (563 mg, 1.76 mmol, 1 equiv), tert-butyl alcohol (3 mL), methanol (3 mL), and 1 N aqueous sodium hydroxide solution (12.0 mL, 12.0 mmol, 6.80 equiv). The mixture was heated at reflux for 24 h, then was cooled to 23 °C. The mixture was partitioned between 0.5 N aqueous sodium hydroxide solution (1 00 mL) and dichloromethane (10 mL). The aqueous layer was separated, then was extracted with dichloromethane (2 x 10 mL) and was acidified to pH ::; 2 by the slow addition of 3 N aqueous hydrochloric acid solution (40 mL). The acidified aqueous layer was saturated with sodium chloride, then was extracted with ethyl acetate (3 x 40 mL). The combined organic extracts were dried over sodium sulfate and were concentrated to afford diacid 49 as a white solid (173 mg, 74%). Diacid 49 was reduced with lithium aluminum hydride (3 equiv) in THF at 0 OCto the corresponding diol, and 1H NMR analysis (400 MHz, CDC13) of the corresponding bis-Mosher esters58 derived from both (R)- and (S)-Mosher's acid established that diacid 49 was of94% ee: mp 104--106 °C. 144 5.03 (br, 1H, HOOC), 2.82 (m, 1H, CH3CH), 2.65 (dd, 1H, J 1 = 16.7 Hz, J2 = 8.3 Hz, one of HOOCCH2 ), 2.38 (dd, 1H, J 1 = 16.7 Hz, J 2 = 5.8 Hz, one of HOOCCH2), 1.20 (d, 3H, J = 7.2 Hz, CH3 CH). 13 C NMR (100 MHz, CD 3 0D) o: 179.2, 175.6, 38.5, 37.0, 17.4. HRMS (EI): Calcd for C5H90 4 (MHt: 133.0501. Found: 133.0504. Analysis: Calcd for C5 H 8 0 4 : C, 45.46; H, 6.10; N, 0. Found: C, 45.86; H, 5.93; N, 0.14. TLC (80% EtOAc-hexanes), R; 49: 0 (PMA). 15: 0.56 (UV, PMA). 145 Chapter 3 Reduction of Pseudoephedrine Amides to Form Highly Enantiomerically Enriched Primary Alcohols 146 Introduction In general, the addition of hydride to the carbonyl group of a tertiary amide affords a tetrahedral intermediate that partitions between CN bond cleavage (leading to the primary alcohol via the aldehyde) and CO bond cleavage (leading to the formation of a tertiary amine by-product via an imminium intermediate, Figure 7). This partitioning is highly H H ""-~ R~N . . . I R' R' 0 II R~w-1 R' R' - H . '-.fOM R' ] R~N__... M-H r I R' --- Figure 7. Divergent pathways for tertiary amide reductions. sensitive to the reaction medium and the nature of the counte1ion "M." Typical metal hydride reagents such as lithium aluminum hydride47 and diborane48 favor the formation of the tertiary amine by-product For this reason, it is often difficult to convert a tertiary amide into the corresponding primary alcohol, a useful synthetic transformation. Important exceptions to this trend include the reagents lithium triethylborohydride (LiBHE13, "superhydride") 49 and 9-BBN,50 developed by Brown and co-workers, and metal amide-borane complexes, introduced by Hutchins et aL 51 and extensively developed by Singaram and co-workers. 52 147 Table7. Reduction with Borane-Lithium Pyrrolidide (LPT) to Form Primary Alcohols 003JL N I CN-BH3-u+ HO~R . R = OH CH3 R' entry substratea R R' THF prod R' temp coq time (h) isol yield (%) isol ee (%) 1 2 11 CH 3 Bn 50 23 6.0 84 ~95 12 CH3 n-Bu 51 23 10.0 81 ~95 3 4 13 CH 3 BOM 52 0 3.0 45 91 Bn 53 54 87 88 6 19 Bn 55 23 23 23 ~95 Bn n-Bu CH3 n-Bu 10.3 5 16 17 89 ~95 7 20 Ph Et 56 23 14.0 87 33b 8 22 i-Pr Bn 57 66 11.0 80 ~95 9 23 t-Bu Bn 58 66 12.0 5 3.1 5.8 ~95 The starting material was in all cases of ~99% de except 13 and 17 were of 98% de, and 16 which was of 97% de. b The predominating enantiomer had inverted configuration relative to the starting material a (20). Reduction of Pseudoephedrine Amides with LAB to Form Primary Alcohols The transformation of pseudoephedrine amides into the corresponding primary alcohols may be considered as a special case within the broader problem of the selective reduction of tertiary amides. Pseudoephedrine amides were found to be inert toward superhydride and 9-BBN. As we reported earlier, 8 the lithium pyrrolidide-borane reagent (lithium pyrrolididotrihydroborate, Li(CH2 ) 4NBH 3 , LPT) of Singaram et aL 52 is effective in transforming certain pseudoephedrine amides into the corresponding primary alcohols selectively and in high yield (Table 7). Subsequently, however, we have encountered difficulties with this reagent in several problematic cases (e.g., entries 3, 7, and 9 within Table 7). For example, the a-benzyloxymethyl-substituted amide 13 suffered partial 148 decomposition during the reduction and the a.-ethyl phenylacetamide substrate 20 provided the primary alcohol 56 in only 33% ee, with inverted configuration! In both cases, the problems encountered were attributed to base-induced epimerization (decomposition) of the intermediate aldehydes. The inverted configuration of the product 56 is believed to arise from enolization of the intermediate aldehyde by a chiral, pseudoephedrine-derived base, followed by enantioselective protonation and reduction. In addition to these examples, highly sterically hindered substrates such as 23 were found to be essentially inert to LPT. We have since reported the development of a new reagent, lithium amidotrihydroborate (LiH2 NBH3 , LAB), that lacks the problematic features of LPT. 53 In our initial report, LAB was prepared by the deprotonation of the commercial solid reagent, borane-ammonia complex/4 using slightly less than 1 equiv of n-butyllithium as base at 0 oc_ In more recent work, we have substantially improved the reagent preparation by the use of 1 equiv of lithium diisopropylamide (LDA) as the base in the reaction. 25 The efficiency of the reduction is greater using LDA as the base and, notably, the product is isolated with much greater facility. Difficulties encountered when n-butyllithium was used as base were traced to the formation of butylboron intermediates in the reaction (particularly in large-scale experiments) and, ultimately, butylboron alkoxide products that were difficult to hydrolyze. This problem could be largely circumvented by conducting the deprotonation with n-butyllithium at -78 °C or, preferably, could be completely avoided by deprotonation with LDA at 0 °C followed by warming to 23 oc_ In the optimized procedure, solid arnmonia-borane complex (4.0 equiv) is added to a solution of LDA (3.9 equiv) in THF at 0 °C, and the resulting suspension is warmed to 23 °C and is held at that temperature for 15-20 min. The cloudy suspension of LAB is then cooled to 0 OC and a solution of the pseudoephedrine amide substrate (1 equiv) in THF is added. Typical reductions proceed to completion within a few hours at 23 °C, although more hindered substr·ates (entry 6, Table 8) may require heating to reflux (66 °C). When the reduction is complete, an acidic 149 Table 8. Reduction of Pseudoephedrine Amides W,ith Lithium Amidotri.hydro borate (LAB) to Form Primary Alcohols 0 x'~'~R LiH 2 NBH 3 R' entry substrate 1 ~CHs 'Ho~R THF product R' ! temp (OC) isol pme (h) yield(%) isol ee (%) 23 1.0 90 299 0 1.3 86 95 23 2.5 92 295 23 1.9 83 92 23 18 86 295 66 10 92 295 23 2 78a 97 23 2 79a 98 0 )(,(+ .: HO~CHs CH 2 C6H5 11 (:?:99% de) GH2 C6 H5 50 0 2 ~CH3 XV+ ,\ CH2 0CHzC6H5 13 (98% de) HO~CHs GH 2 0CHzC6H5 52 0 3 4 ~ CH3 Xy+ ,\ HO~CH 3 CHzCsHs 19 (::::99% de) GH 2C6H5 55 ~ Xy+ .: CH 2 CH 3 20 (:?:99% de) 0 5 CHs xHcHs CH 2 C6H5 ~ HO CHs HO~CHs CH2CsHs 57 22 (:?:99% de) 6 J::XCHs Xo/+ ,\ CH3 CHzCsHs 23 (::::99% de) ~ GH 2 CH 3 56 ~CH 3 HO ~ CH 3 CH 2 C6H5 58 0 7 X~CHs HO~CHs CHs CHs 27 (97%de) CH3 CHs 59 0 8 ~ Xv,\ ,\ CH 3 CH3 CH 3 28 (98% de) HO~CH 3 CHs CHs 60 150 9 x~Ph CHa CHa 29 (98% de) HO~Ph 23 2 95 98 23 2 96 96 23 2 93 99 23 2 93 97 23 2 91 97 23 2 89 99 CH 3 CH 3 61 0 10 Xy~Ph HO~Ph CHa CHa CHa CHa 30 (97% de) 62 x~Ph HO~Ph 0 11 CHa CHa CHa 31 (99% de) CH 3 CH 3 CH 3 63 0 12 :<y~Ph HO~Ph 32 (97% de) 64 CH 3 CH 3 CH 3 CH 3 CH 3 CH 3 0 13 :<y~Ph CH CH CH HO~Ph 33 (97% de) 65 3 3 3 CHa CHa CHa 0 14 x~Ph CH CH CH HO~Ph 34 (99% de) 66 3 3 3 CH 3 CH 3 CH 3 a The yield was lowered due to the volatility of the product. aqueous work-up procedure provides a mixture of the desired alcohol and a (different) alkoxy boron species. Fortunately, this alkoxy boron species is exceedingly labile toward silica gel and undergoes quantitative cleavage to the alcohol dming flash column chromatographic purification. Where flash column chromatography is not an acceptable means of purification (e.g., on large scale, where distillation of the alcohol might be preferable), the alkoxy boron species can be cleaved rapidly and quantitatively by treatment with 1 N aqueous sodium hydroxide solution at 23 °C for 30-60 min. This modified LAB reduction procedure has proven to be highly effective for the synthesis of a wide variety of highly enantiomerically enriched primary alcohols from the corresponding pseudoephedrine amide precursors. As evident from the examples of Table 151 8, little to no epimerization of the u-stereocenter is observed. Generally, <4% of the tertiary amine by-product is produced if care is taken to use at least 4 molar equiv of LAB in the reaction. Tertiary amine formation can be more extensive if less reductant is employed.53 The tertiary amine generally exhibits an R1 value comparable to that of the product alcohol, and is most conveniently removed by extraction with aqueous acid. When an acid wash is not desirable (for acid-sensitive substrates or for tertiary amine hydrochlorides that are not water soluble), the tertiary amine by-product can be readily separated by flash column chromatography using triethylamine-pretreated silica geL Reductions of pseudoephedrine amides with LAB are much more rapid than reductions with LPT. For example, LAB reduction of substrate 11 occurs in 1 h at 23 CC (90% yield) whereas LPT reduction of 11 requires 6 h at 23 CC (84% yield). In addition, LAB appears to have a lesser tendency to effect base-induced side reactions compared to LPT. As a result, highly epimerizable aldehyde intermediates can be traversed without substantial loss of stereochemical integrity. For example, reduction of the u- benzyloxymethyl-substituted amide 13 (98% de) with LAB formed the corresponding alcohol in 86% yield and 95% ee and reduction of the phenylacetamide 20 (~99% de) with LAB provided (S)-2-phenyl-1-butanol in 83% yield and 92% ee. In addition, LAB is found to be far superior to LPT for the reduction of sterically hindered amides. Thus, the substrate 22 was found to be inert to LPT at 23 CC but was cleanly reduced with LAB at 23 oc (entry 5, Table 8, 86% yield of alcohol, ~95% ee). More dramatically, the highly hindered substrate 23 proved to be virtually inert toward LPT, even in refluxing THF (Table 7, entry 9, 12 h, 5% yield), but was readily reduced with LAB (Table 8, entry 6, 10 h, 66 °C, 91% yield, ~5% ee). Reduction of Tertiary Amides with LAB to Form Primary Alcohols Our success with LAB in the reduction of pseudoephedrine amides prompted us to 152 Table 9. Use of LAB for the Reduction of Tertiary Amides to Primary Alcohols entry substrate temp (OC) time (h) isol yield alcohol (%) isol yield 3°amine (%) 1 CHa(CH 2)1aCONEt2 23 1.3 94 <5 /JEt 23 16.0 87 8 CH 3 (CH~ 10 CON(i-Prh 23 6.0 68 28 66 1.7 47 51 2 2 3 /J(~Pr), 4 investigate whether LAB was a superior reagent for the reduction of tertiary amides in general (Table 9). 53 N,N-Diethyldodecanamide formed 1-dodecanol in 94% yield (1.3 hat 23 °C) with LAB (4.0 equiv), whereas LPT is repmted to give the te1tiary amine, N,Ndiethyldodecanamine, in 71% yield_m T11e reduction of N,N-diethyldodecanamide with lithium triethylborohydride is not reported, but reduction of N,N-diethylbutanamide, a substrate of similar steric and electronic character, is repmted to proceed in only 50% yield at 25 OC (2.2 equiv of hydride). 49 Even the hindered 1-adamantanecarboxylic acid N,Ndiethylamide (entry 2) is reduced to the primary alcohol (88%) with LAB. In exploring the limits of tertiary amide reductions with LAB, we find that substantial amounts of tertiary amine by-products are formed with N,N-diisopropylamides as substrates (entries 3 and 4, Table 9). This is in keeping with Hutchins' observations that substrates with N- substituents of increasing steric demand tend to favor fonnation of the te1tiary amine with 153 sodium dimethylamidotrihydroborate as reductant. 51 The fact that the N,N- diisopropylamides of entries 3 and 4 are reduced at all with LAB is testimony to the high nucleophilicity of this reagent; lithium triethylborohydride, for example, does not react with N,N-diisopropylamides. 49 It should be noted that while the modified procedure for the preparation of LAB (deprotonation of borane-ammonia complex with LDA instead of n-butyllithium) results in a cleaner reduction and a more facile work-up procedure, the modified procedure is less effective in the conversion of N,N-diisopropylamides to primary alcohols. Reduction of the N,N-diisopropylamide of entry 4, Table 9, using the modified procedure for the preparation of LAB, afforded a 37% yield of 1adamantanemethanol (cf. 47% yield when using n-butyllithium as the deprotonating agent), with a corresponding increase in the yield of the te1tiary amine by-product. The decreased yield of primary alcohol may be due simply to product inhibition. Diisopropylamine is the stoichiometric by-product of the deprotonation of borane-ammonia complex with LDA, and it is also the stoichiometric by-product in the transfonnation of an N,N-diisopropylamide to the co1responding primary alcohoL 11 B NMR Studies of LAB To our knowledge, though LAB has been the subject of two computational studies, 55 it had not been prepared in the laboratory prior to our initial report. Evidence that the reaction of n-butyllithium with borane-ammonia complex forms LAB comes from 1 H-decoupled 11 B NMR spectroscopy, where a sharp singlet resonating at -22 ppm (BF3 •0E12, reference) is observed. This value corresponds well with known amide-borane complexes52a (but not, e.g., with LiBuBH3, which resonates at -29 ppm). 56 In addition, when the solid borane-ammonia reagent and neopentyllithium were combined in THF-d8 at 23 °C, the same singlet at -22 ppm was observed in the 11 B NMR spectrum and neopentane was formed cleanly (13 C NMR). Evidence that using the modified LAB preparation (LDA as the deprotonating agent in lieu of n-butyllithium) does not produce 154 lithium diisopropylamidotrihydroborate (LDT) comes from comparative studies of the reactivity of the two metal amide borane complexes. LDT was prepared by the literature procedure: 52b borane-tetrahydrofuran complex was complexed with diisopropylamine to form a stable amine-borane complex, and deprotonation of this amine-borane complex with n-butyllithium formed LDT. Pseudoephedrine amide 23 was inert to LDT even in refluxing THF (isolated yield of alcohol 58 was <5%). However, the reducing agent formed in situ by combining borane-ammonia complex with LDA does reduce amide 2 3 (Table 6, entry 6). Furthermore, this species reverts on silica gel to borane-ammonia complex, and not, e.g., to borane-diisopropylamine complex (as dete1mined by TLC analysis). Reduction of Pseudoephedrine Amides Involving In Situ Borane-Amine Complexation The hydrosulfate salt formed by N --7 0 acyl transfer under acidic conditions was also investigated as an intermediate in a procedure to form highly enantiomerically emiched primary alcohols. Using the a-benzyloxymethyl-substituted amide 13 as a model substrate, attempts to reduce its cmresponding N --7 0 acyl transfer hydrosulfate salt using a variety of metal-hydride reducing agents (lithium aluminum hydride, diisobutylaluminum hydride, sodium bis(2-methoxyethoxy)aluminum hydride, lithium triethylborohydride) all gave significant quantities of a pseudoephedrine aminal by-product or an ether by-product (Scheme XI), both of which result from either 0 --7 N acyl transfer or the tetrahedral intermediate that would lead to 0 --7 N acyl transfer. The first step to either of these byproducts is probably metal hydride-induced deprotonation of the ammonium te1minus to generate a free (nucleophilic) amine. 155 Scheme XI Using a procedure analogous to the hydrolysis of pseudoephedrine amides involving in situ borane-amine complexation (pp. 116-119), the amine-borane complex was reduced with diisobutylaluminum hydride to afford the alcohol 52 in 86% yield and 93% ee (Scheme XII, cf. 86% yield, 95% ee with LAB). This same sequence of steps was used to transform phenylacetamide 20 to alcohol 56 in 95% ee (cf. 90% ee with LAB). In the case of amide 20, the product alcohol (56) had the same R1 as the pseudoephedrine-borane complex which was liberated during the reaction, rendering flash column chromatographic purification ineffective. Pseudoephedrine-borane complex Scheme XII H3 0 N}yCH3 OH = I CH3 CH20CH2C6H5 13 DIBAL-H HO~CH3 CH20CH2 CsHs 52: 86% yield, 93% ee 156 can be decomposed with trifluoroacetic acid in methanol to allow for flash column chromatographic purification, but this was not conducted for alcohol 56, since the higher ee observed with this procedure (than with LAB) did not offset the much more arduous procedures required to effect this reductive transfonnation. Conclusion In summary, we have demonstrated that LAB is a highly nucleophilic hydride source that is easily prepared from readily available, commercial materials. Its efficacy for the particular application at hand, the selective reduction of a tertiary amide to the corresponding alcohol, appears to be supelior to any existing reagent. 157 Experimental Section General Procedures. All non-aqueous reactions were performed in flame-dried round-bottomed or modified Schlenk (Kjeldahl shape) flasks, equipped with a magnetic stirring bar and fitted with a rubber septum under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula unless otherwise noted. concentrated by rotary evaporation at -25 Torr. . Organic solutions were Flash column chromatography was performed as described by Still et al. 38 employing 230-400 mesh silica geL Analytical thin-layer chromatography was performed using glass plates precoated with 0.25-mm 230400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran was distilled under nitrogen from sodium benzophenone ketyl. Dichloromethane, diisopropylamine, triethylamine, and pyrrolidine were distilled under nitrogen from calcium hydride. The molarity of n-butyllithium was determined by titration against diphenylacetic acid as an indicator (average of three determinations). 40 Borane-ammonia complex and neopentyllithium were stored and transferred under nitrogen. Solvents used for flash column chromatography were reagentgrade. Instrumentation. Melting points are uncorrected. Infrared data are presented as follows: frequency of absorption (cm-1), intensity of absorption (br =broad, s =strong, m =medium). 1 H NMR spectra were recorded at 400 or 300 MHz, and 13 C NMR spectra were recorded at 100 or 7 5 MHz; chemical shifts are expressed in parts per million (8 scale) downfield from tetramethylsilane. 1H NMR chemical shifts are referenced to the signal for residual hydrogen in the NMR solvent (CHC13: 8 7.26, C6HD5 : 8 7.15) or to tetramethylsilane. Data are presented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, sp = septet, m = multiplet), integration, and coupling constant in Hertz. 13 158 C NMR chemical shifts are referenced to the carbon signal for the solvent (CDC13 : 8 77.0, C 6D 6 : 8 128.0). 11 B spectra were recorded at 128 MHz and the chemical shifts are expressed in parts per million (8 scale) downfield from both trimethylborate and boron trifluoride etherate. Mass spectrometry was performed at the California Institute of Technology or at the University of California at Irvine. Combustion analyses were performed by Quantitative Technologies Incorporated. Chiral capillary gas chromatography (GC) analysis was canied out using an Alltech Chirasil-Val chiral fused silica capillary column, under isothennal conditions, with a column head pressure of 17 psi. High performance liquid chromatography (HPLC) was conducted using a Chiralcel OD column. 159 THF, 23 oc 00% CR)-6-Methyl Benzenepropanol 50 A solution of n-butyllithium in hexanes (2.34 M, 53.5 mL, 125 mmol, 3.90 equiv) was added to a solution of diisopropylamine (18.9 mL, 125 mmol, 4.20 equiv) in tetrahydrofuran (150 mL) at -78 °C. The resulting solution was stin·ed at -78 CC for 10 min, at 0 °C for 5 min, then was cooled to -78 °C. Borane-ammonia complex (90%, 4.41 g, 129 mmol, 4.00 equiv) was added in one portion, and the suspension was warmed to 0 0 C. The mixture was stirred at 0 °C for 20 min, at 23 CC for 20 min, then was cooled to 0 °C. A solution of amide 11 (10.0 g, 32.1 mmol, 1 equiv) in tetrahydrofuran (150 mL, followed by a 5-mL rinse) was added via cannula over ~4 min. The reaction mixture was warmed to 23 CC and was held at that temperature for 50 min, then was cooled to 0 'C where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (350 mL). The biphasic mixture was stirred at 23 CC for 30 min, then was extracted with three 150-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (50 mL) and brine (50 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography (43% ether-petroleum ether) afforded alcohol 50 as a colorless liquid (4.35 g, 90%). Chiral HPLC analysis57 (Chiralcel OD) of alcoholS 0 established that alcohol 50 was of~99% ee. 160 7.0-7.2 (m, 5H, aromatic), 3.15 (m, 2H, HOCH 2), 2.62 (dd, 1H, 1 1 = 13.3 Hz, 12 = 6.2 Hz, one of PhCH 2 ), 2.22 (dd, 1H, 1 1 = 13.3 Hz, 12 = 8.0 Hz, one of PhCH 2), 1.70 (m, 1H, CH 3CH), 0.77 (d, 3H, J = 6.7 Hz, CH 3), 0.62 (t, 1H, J = 5.2 Hz, OH). C NMR (7 5 MHz, CDC13) o: 13 140.6, 129.0, 128.2, 125.7, 67.4, 39.6, 37.7, 16.4. FTIR (neat, cm-1): 3332 (br, s, OH). Analysis: Calcd for C 10 H 140: C, 79.96; H, 9.39; N, 0. Found: C, 79.67; H, 9.05; N, <0.05. TLC (60% EtOAc-hexanes), R; 50: 0.56 (UV, PMA). 11: 0.21 (UV, PMA). 161 THF, 23 oc 84% (R)-!}Methyl Benzent41ropanol 50 A 100-mL flask was immersed in an ice bath and was charged sequentially with pyrrolidine (0.800 mL, 9.63 mmol, 3.00 equiv) and borane-tetrahydrofuran complex (1.0 Min THF, 9.63 mL, 9.63 mmol, 3.00 equiv). The solution was warmed to 23 °C, and was held at that temperature for 1 h, then was cooled to 0 °C. A solution of n-butyllithium in hexanes (1.71 M, 5.63 mL, 9.63 mmol, 3.00 equiv) was added to the cold solution of borane-pyrrolidine complex, and the resulting solution was stirred at 0 °C for 30 min. A solution of amide 11 (1.00 g, 3.21 mmol, 1 equiv) in tetrahydrofuran (9 mL, followed by a 1-mL rinse) was added via cannula. The reaction mixture was stirred at 23 °C for 6 h before excess hydride was quenched by the addition of 3 N aqueous hydrochloric acid solution (15 mL). The mixture was partitioned between aqueous 1 N hydrochloric acid solution (350 mL) and ether (50 mL). The aqueous layer was separated and extracted with three 50-mL portions of ether. The combined ether extracts were washed with two 25-mL portions of a 1:1 mixture of brine and 1 N aqueous hydrochlor4; acid solution, then were concentrated. The residue was stirred with 1 N aqueous sodium hydroxide solution (100 mL) at 23 OC for 30 min and the mixture was extracted with ether (3 x 30 mL). The combined ether extracts were washed with two 10-mL portions of a 1:1 mixture of brine and 1 N aqueous sodium hydroxide solution, then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (35% etherpetroleum ether) afforded alcohol 50 as a colorless liquid (405 mg, 84%). Acylation of alcohol 50 (9.0 mg, 0.060 mmol, 1 equiv) with the Mosher acid chloride (-0.17 mmol, 162 ~2.8 equiv) and triethylamine (42 ).l.L, 0.30 mmol, 5.0 equiv) in dichloromethane (1.5 rnL) at 23 °C for 10 h, followed by 1H NMR analysis (300 MHz, C 6D 6) of the resulting Mosher ester derivative53 established that alcohol SO was of ~95% ee. 58 The Mosher chloride (-0.17 mmol, -2.8 equiv) was prepared in situ by stirring Mosher's acid (40 mg, 0.17 mmol, 2.8 equiv), oxalyl chloride (19 J.LL, 0.22 mmol, 3.7 equiv), and N ,Ndimethylformamide (2.0 ).l.L, 0.026 mmol, 0.43 equiv) in dichloromethane (1 mL) at 23 CC for 30 min, followed by removal of dichloromethane and e~cess oxalyl chloride under reduced pressure (0.5 mm Hg) at 0 °C for 30 min. Spectroscopic data of alcohol S 0 were identical to those listed above. HRMS (FAB): Calcd for C 10H 14 0 (Mt: 150.1045. Found: 150.1047. TLC (60% EtOAc-hexanes), R; SO: 0.56 (UV, PMA). 11: 0.21 (UV, PMA). 163 HO~CH3 CH2(CH2)2CH3 51 (R)-2-Methyl-1-hexanol 51 Alcohol 51 was prepared by the reduction of amide 12 with LPT, as described above for the alcohol 50. Thus, treatment of amide 12 (2.00 g, 7.21 mmol, 1 equiv) with LPT (5.41 mmol, 3.00 equiv) at 23 OC for 10 h afforded alcohol 51 as a colorless liquid (170 mg, 81 %) after purification by flash column chromatography (40% ether-petroleum ether). High resolution 1H NMR analysis (300 MHz, C6D6) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 51 was of~95% ee. 1 H NMR (300 MHz, C(}l)6) 8: 3.19 (m, 2H, HOCH 2), 0.92-1.44 (m, 7H, CH 3 CH 2 CH 2 CH 2 CH), 0.87 (t, 3H, J = 6.9 Hz, CH 3CH 2), 0.83 (d, 3H, J = 6.6 Hz, CH 3 CH), 0.69 (s, 1H, OH). 13 C NMR (7 5 MHz, CDCl~ 8: 68.0, 36.0, 33.2, 29.6, 23.4, 16.8, 14.3. FTIR (neat, cm-1): 3339 (br, s, OH). HRMS (FAB): Calcd for c;H14 (M-H2 0t: 98.1096. Found: 98.1099. TLC (60% ether-pet ether), R; 51: 0.43 (PMA). 12: 0.32 (UV, PMA). 164 HO---yCHa THF, 0 oc ffi% CH 2 0CH 2 C 6 Hs 52 (S)-3-Benzyloxy-2-methylpropanol 52 A solution of n-butyllithiurn in hexanes (2.38 M, 1.22 mL, 2.90 mmol, 3.90 equiv) was added to a solution of diisopropylamine (0.439 mL, 3.13 mmol, 4.20 equiv) in tetrahydrofuran (2.5 mL) at -78 °C. The resulting solution was stirred at -78 OC for 10 min, at 0 oc for 5 min, then was cooled to -78 °C. Borane-ammonia complex (90%, 102 mg, 2.98 mmol, 4.00 equiv) was added in one portion, and the suspension was warmed to 0 °C. The mixture was stirred at 0 °C for 20 min, at 23 °C for 20 min, then was cooled to 0 °C. A solution of amide 13 (255 mg, 0.746 mmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stirred at 0 OC for 1.3 h, then excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (10 mL). The mixture was extracted with four 9-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (3 mL) and brine (3 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography (gradient elution of ether-petroleum ether, 40 ~ 50%) afforded alcohol 52 as a colorless liquid (1.16 mg, 86%). High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 52 was of 95% ee. 165 7.0-7.25 (rn, 5HJ aromatic), 4.21 (s, 2H, PhCH 2~, i J. i' 3.46 (d, 2H, J = 8.9 Hz, fCH 3CHCH2 0), 3.20 (rn, 2H, HOCH2 ), 1.86 (rn, 1H, CH3 CH), 0.73 (d, 3H, J = 6.9 Hz, CH3). 13 C NMR (7 5 MHz, CDCl:J 8: 138.0, 128.4, 127.6, 147.5, 75.2, 73.3, 67.6, 35.6, 13.4. 3388 (br, s, OH). HRMS (EI): Calcd for C 11H 16 0 2 (Mt: 180.1150. Found: 180.1155. TLC (60% EtOAc-hexanes), R; 52: 0.43 (UV, PMA). 13: 0.19 (UV, PMA). 166 HO~CH3 CH20CH2CsHs 52 (S)-3-Benzyloxy-2-methyl:propanol 52 Alcohol 52 was prepared by the reduction of amide 13 with LPT, as described above for the alcohol 50. Thus, treatment of amide 13 (100 mg, 0.293 mmol, 1 equiv) with LPT (1.17 mmol, 4.20 equiv) at 0 °C for 3 h afforded alcohol 52 as a colorless liquid (23.5 mg, 45%) after purification by flash column chromatography (gradient elution of ether-petroleum ether, 40 ~50%). High resolution 1H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative/8 prepared as described above for alcohol 50, established that alcohol 52 was of 91% ee. Spectroscopic data of alcohol 52 were identical to those listed above. TLC (60% EtOAc-hexanes), Ri 52: 0.43 (UV, PMA). 13: 0.19 (UV, PMA). benzyl alcohol: 0.48 (UV, PMA). 167 HO~CHs 3) DIBAL-H CH 2 0CH2 CsHs 52 86% CS)-3-Benzyloxy-2-methylpropanol 52 An ice-cooled solution of 18 N aqueous sulfuric acid (2 mL) was added to a solution of amide 13 (500 mg, 1.46 mmol, 1 equiv) in dioxane (2 mL) at 10 °C. The biphasic mixture was warmed to 23 OC and held at that temperature for 2 hours. The mixture was partitioned between brine (35 mL) and ethyl acetate (35 mL). The aqueous layer was separated and saturated with sodium chloride, then was extracted with ethyl acetate (3 x 35 mL). The combined organic fractions were dried over sodium sulfate and were concentrated to yield a fm.e white powder. tetrahydrofuran (8 mL) and cooled to 0 °C. The powder was dissolved in A solution of lithium borohydride in tetrahydrofuran (2.0 M, 0.880 mL, 1.75 mmol, 1.20 equiv) was added slowly via syringe, resulting in vigorous gas evolution. The reaction mixture was stirred at 0 OC for 5 min, after which time bubbling had ceased, and a solution of diisobutylaluminum hydride in toluene (1.0 M, 4.38 mL, 4.38 mmol, 3.00 equiv) was added dropwise via syringe. The mixture was stirred at 0 OC for 15 min, then excess hydride was quenched by the slow addition of 3 N aqueous hydrochloric acid solution (5 mL). The mixture was partitioned between 1 N aqueous hydrochloric acid solution (100 mL) and ethyl acetate (35 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 35 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. The residue was dissolved in a solution of methanol (12 mL) and trifluoroacetic acid (2.8 mL, 36 mmol, 25 equiv), and the mixture was stirred overnight at 23 °C. The reaction mixture was partitioned between ethyl acetate (200 mL) and saturated aqueous sodium bicarbonate solution (20 mL). The organic layer was separated and extracted sequentially with 168 saturated aqueous sodium bicarbonate solution (2 x 20 mL), 3 N aqueous hydrochloric acid solution (2 x 20 mL), and brine (10 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (40 -7 50%) afforded alcohol 52 as a colorless liquid (225 mg, 86% yield from 13). High resolution 1H NMR spectroscopy (300 MHz, CDC13) of the corresponding Mosher ester derivative/8 prepared as described above for alcohol SO, established that alcohol 52 was of 93% ee. Spectroscopic data of alcohol 52 were identical to those listed above. 52: 0.58 (UV, PMA). N -7 0 acyl transfer: 0.13-0.26 streak (UV, PMA). 13: 0.38 (UV, PMA). 169 THF, 23 oc 87% CS)-6-Methyl Benzenepropanol 53 Alcohol 53 was prepared by the reduction of amide 16 with LPT, as described above for the alcohol 50. Thus, treatment of amide 16 (500 mg, 1.61 mmol, 1 equiv) with LPT (4.82 mmol, 3.00 equiv) at 23 CC for 10.3 h afforded alcohol 53 as a colorless liquid (210 mg, 87%) after purification by flash column chromatography (35% etherpetroleum ether). High resolution 1 H NMR analysis (300 MHz, C 6D 6) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 53 was of ~95% ee. Spectroscopic data of alcohol 53 were identical to those of its enantiomer, (R)-~-methyl benzenepropanol (50). HRMS (FAB): Calcd for C 10H 14 0 (Mt: 150.1045. Found: 150.1046. TLC (50% EtOAc-hexanes), R; 53: 0.51 (UV, PMA). 16: 0.24 (UV, PMA). 170 00;~CHzPh OH HO~CH2Ph THF, 23 oc CHs C~ (C~)zCHs 17 88% CH2(CHmCHs 54 CS)-6-Butyl Benzen<4>ropanol 54 Alcohol 54 was prepared by the reduction of amide 17 with LPT, as described above for the alcohol 50. Thus, treatment of amide 17 (201 mg, 0.569 mmol, 1 equiv) with LPT (1.71 mmol, 3.00 equiv) at 23 CC for 3.1 h afforded alcohol 54 as a colorless liquid (96 mg, 88% yield) after purification by flash column chromatography (25% ethyl acetate-hexanes). High resolution 1 H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 54 was of ~95% ee. 171 7.0-7.3 (m, 5H, aromatic), 3.25 (d, 2H, J = 5.1 Hz, HOCH 2), 2.59 (dd, 1H, J = 13.5 Hz, 7.6 Hz, one of PhCH2 ), 2.48 (dd, lH, J = 13.5 Hz, 6.5 Hz, one of PhCH 2 ), HOCH 2CHCH2), 1.60 1.31 (m, 1H, one of (m, 1H, one of HOCH 2 CHCH2 ), 1.20 (m, 4H, CH 3 CH 2CH2 ), 0.84 (m, 3H, CH 3). 140.8, 129.1, 128.1, 125.7, 64.6, 42.4, 37.5, 30.3, 29.0, 22.9, 14.0. FTIR (neat, cm-1): 3342 (br, m, OH). HRMS (FAB): Calcd for C 13H 20 0 (Mt: 192.1515. Found: 192.1508. TLC (40% EtOAc-hexanes), R; 54: 0.47 (UV, PMA). 17: 0.22 (UV, PMA). 172 HO~CHa THF, 23 oc CH2CsHs 92% 55 CR)-6-Butyl Benzenepropanol 55 A solution of n-butyllithium in hexanes (2.37 M, 4.78 mL, 11.3 mmol, 4.00 equiv) was added to a suspension of borane-ammonia complex (90%, 408 mg, 11.9 mmol, 4.20 equiv) in tetrahydrofuran (10 mL) at 0 °C. The suspension was warmed briefly to 23 °C, then was cooled to 0 °C. A solution of amide 19 (1.00 g, 2.83 mmol, 1 equiv) in tetrahydrofuran (10 mL, followed by a 2-mL rinse) was added via cannula, and the mixture was warmed to 23 °C. The mixture was stiiTed at 23 °C for 2.5 h, then excess hyd1ide was quenched by the cautious addition of 1 N aqueous hydrochlmic acid solution (120 mL). The mixture was extracted with four 40-mL portions of ether. The combined ether extracts were washed with 1 N aqueous hydrochloric acid solution (10 mL), then were dried over sodium sulfate and were concentrated. The residue was stilTed in 1 N aqueous sodium hydroxide solution (150 mL) at 23 OC for 1 h. The mixture was extracted with ether (40 mL), then was saturated with sodium chloride and was extracted with two 40-mL portions of ether. The combined ether extracts were washed sequentially with 1 N aqueous hydrochloric acid solution (2 x 40 mL) and b1ine (10 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (30 ~ 35%) afforded alcohol 55 as a colorless liquid (500 mg, 92%). High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 55 was of ;;:::95% ee. Spectroscopic data of alcohol 55 were identical to those of its enantiomer, (S)-j3-butyl benzenepropanol (54). TLC (50% EtOAc-hexanes), Rf 55: 0.55 (UV, PMA). 19: 0.38 (UV, PMA). 173 H3 0 0-BH3-u+ N~CH3 I HO~CH3 .:. THF, 23°C 0 H CH3 CH2CsHs CH2CsHs 55 19 (R)-~-Butyl Benzenepropanol 55 Alcohol 55 was prepared by the reduction of amide 19 with LPT, as described above for the alcohol 50. Thus, treatment of amide 19 (500 mg, 1.41 mmol, 1 equiv) with LPT (4.24 mmol, 3.00 equiv) at 23 CC for 5.8 h afforded alcohol 55 as a colorless liquid (243 mg, 89%) after purification by flash column chromatography (25% ethyl acetate-hexanes). High resolution 1 H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative,5 8 prepared as described above for alcohol 50, established that alcohol 55 was of~95% ee. Spectroscopic data were identical to those of its enantiomer, (S)-J3-butyl benzenepropanol (54). HRMS (FAB): Calcd for C 13H 20 0 (Mt: 192.1515. Found: 192.1508. TLC (50% EtOAc-hexanes), R; 55: 0.55 (UV, PMA). 19: 0.38 (UV, PMA). 174 00;3y() 0 H CH3 CH2CH3 2) THF, 23 oc 83"/o CS)-13-Ethyl Benzeneetbanol 56 A solution of n-butyllithium in hexanes (2.39 M, 0.880 mL, 2.10 mmol, 3.90 equiv) was added to a solution of diisopropylamine (0.317 mL, 2.26 mmol, 4.20 equiv) in tetrahydrofuran (2 mL) at -78 °C. The resulting solution was stirred at -78 OC for 10 min, at 0 OC for 5 min, then was cooled to -78 °C. Borane-ammonia complex (90%, 74 mg, 2.16 mmol, 4.00 equiv) was added in one portion, and the suspension was warmed to 0 °C. The mixture was stirred at 0 oc for 20 min, at 23 OC for 20 min, then was cooled to 0 °C. A solution of amide 20 (168 mg, 0.539 mmol, 1 equiv) in tetrahydrofuran (1.5 mL, followed by a 0.5~mL rinse) was added via cannula. The reaction mixture was warmed to 23 OC and was held at that temperature for 1.9 h, then was cooled to 0 OC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (8 mL). The mixture was extracted with four 7-mL portions of ether. The combined ether extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (3 mL) and brine (3 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography (40% ether-petroleum ether) afforded alcohol 56 as a colorless liquid (67 mg, 83%). Acylation of the product with the (R)Mosher acid chloride according to the method described above for alcohol 50 afforded a mixture of Mosher ester derivatives in 92% de as determined by 1H NMR analysis, establishing that alcohol 56 was of 92% ee.58 The major diastereomer was shown to be identical to the Mosher ester derivative prepared from the acylation of authentic (S)-~-ethyl benzeneethaJ.?-ol by high resolution 1H NMR analysis (400 MHz, C 6D 6). An authentic 175 sample of (S)-J3-ethyl benzeneethanol was prepared by reduction of (S)-2-phenylbutyric acid with lithium aluminum hydride in THF at 0 oc_ 7.0--7.2 (m, 5H, aromatic), 3.48 (m, 2H, HOCH2 ), 2.44 (m, 1H, PhCH), 1.62 (m, 1H, one of CH 3 CH2 ), 1.41 (m, 1H, one of CH 3 CH2 ), 0.91 (t, 1H, OH), 0.72 (t, 3H, J = 7.4 Hz, CH3 ). 13 C NMR (7 5 MHz, CDClJ 8: 142.2, 128.6, 128.1, 126.6, 67.3, 50.4, 24.9, 11.9. FTIR (neat, cm-1): 3354 (br, s, OH). HRMS (FAB): Calcd for C 10H 14 0 (Mt: 150.1045. Found: 150.1047. TLC (50% EtOAc-hexanes), R; 56: 0.52 (UV, PMA). 20: 0.33 (UV, PMA). 176 ~ H39 N~ I THF, 23 oc :: 0 H CH3 CH2CH3 2) CS)-6-Ethyl Benzeneethanol 56 Alcohol 56 was prepared by the reduction of amide 20 with LPT, as described above for the alcohol 50. Thus, treatment of amide 20 (500 mg, 1.61 mmol, 1 equiv) with LPT (4.82 mmol, 3.00 equiv) at 23 CC for 14 h afforded alcohol 56 as a colorless liquid (210 mg, 87%) after purification by flash column chromatography (40% etherpetroleum ether). High resolution 1 H NMR analysis (400 MHz, C6D 6 ) of the corresponding Mosher ester derivative, as described in the preceding procedure, established that the reduction of amide 20 with LPT afforded (R)-~-ethyl benzeneethanol in 33% ee. Spectroscopic data of alcohol 56 were identical to those listed above. TLC (50% EtOAc-hexanes), R; 56: 0.52 (UV, PMA). 20: 0.33 (UV, PMA). 177 CH 3 THF, 23 oc HOYCHs CH 2 C6 H 5 fiT CS)-13--Cl-Methylethyl)benzenepropanol 57 A solution of n-butyllithium in hexanes (2.34 M, 1.48 mL, 3.47 mmol, 3.90 equiv) was added to a solution of diisopropylamine (0.523 mL, 3.73 mmol, 4.20 equiv) in tetrahydrofuran (4 mL) at-78 °C. The resulting solution was stin·ed at -78 OC for 10 min, at 0 °C for 5 min, then was cooled to -78 °C. Borane-ammonia complex (90%, 122 mg, 3.56 mmol, 4.00 equiv) was added in one portion, and the suspension was warmed to 0 °C. The mixture was stirred at 0 oc for 20 min, at 23 OC for 20 min, then was cooled to 0 °C. A solution of amide 22 (302 mg, 0.890 mmol, 1 equiv) in tetrahydrofuran (3 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was warmed to 23 OC and was held at that temperature for 18 h, then was cooled to 0 °C where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (10 mL). The mixture was extracted with four 9-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochlmic acid solution (3 rn.L) and brine (3 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (20 ~ 40%) afforded alcohol 57 as a colorless liquid (137 mg, 86% ). High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 57 was of~95% ee. 178 7.1-7.4 (rn, 5H, aromatic), 3.55 (d, 3H, J = 5.6 Hz, HOCH 2), 2.71 (dd, J = 13.7, 5.5 Hz, one of PhCH2 ), 2.51 (dd, 1H, J = 13.7, 9.1 Hz, one of PhCH 2 ), 1.86 (rn, 1H, HOCH 2CH), 1.67 (rn, 1H, CH(CH3 ) 2 ), 0.98 (d, 3H, J = 5.6 Hz, CH 3), 0.96 (d, 3H, J = 5.6 Hz, CH 3 ). 13 C NMR (7 5 MHz, CDCI;, 8: 141.4, 129.0, 128.3, 125.8, 62.9, 48.8, 34.4, 27.8, 19.7, 19.4. FTIR (neat, crn-1): 3354 (br, rn, OH). HRMS (EI): Calcd for C 12H 18 0 (Mt: 178.1358. Found: 178.1357. TLC (50% EtOAc-hexanes), R; 57: 0.52 (UV, PMA). 22: 0.33 (UV, PMA). 179 CH3 THF, 66 oc HOYCH3 CH2C6Hs ff)% fil (S)-~-(1-Methylethyl)benzenepropanol 57 Alcohol 57 was prepared by the reduction of amide 22 with LPT, as described above for the alcohol 50. Thus, treatment of amide 22 (100 mg, 0.295 mmol, 1 equiv) with LPT (1.18 mmol, 4.00 equiv) at 66 OC for 11 h afforded alcohol 57 as a colorless liquid (42.0 mg, 80%) after purification by flash column chromatography (gradient elution of ether-petroleum ether, 20 -7 40%). High resolution 1H NMR analysis (300 MHz, CDC13) of the corresponding Mosher ester derivative, 58 prepared as described above for alcohol 50, established that alcohol 57 was of2':95% ee. Spectroscopic data of alcohol 57 were identical to those listed above. TLC (50% EtOAc-hexanes), Rf 57: 0.52 (UV, PMA). 22: 0.33 (UV, PMA). 180 Hsq CHs THF, 66 oc HoYcHs CH2CsHs 5B (S)-~(1. 1-Dimethylethyl)benzenepropanol 58 A solution ofn-butyllithium in hexanes (2.31 M, 4.78 mL, 11.0 mmol, 3.90 equiv) was added to a solution of diisopropylamine (1.67 mL, 11.9 mmol, 4.20 equiv) in tetrahydrofuran (11 mL) at -78 °C. The resulting solution was stirred at -78 °C for 10 min, at 0 °C for 5 min, then was cooled to -78 °C. Borane-ammonia complex (90%, 388 mg, 11.3 mmol, 4.00 equiv) was added in one portion, and the suspension was wanned to 0 0 C. The mixture was stirred at 0 °C for 20 min, at 23 OC for 20 min, then was cooled to 0 °C. A solution of amide 23 (1.00 g, 2.83 mmol, 1 equiv) in tetrahydrofuran (9 mL, followed by a 2-mL rinse) was added via cannula. The reaction mixture was wanned to 66 °C and was held at that temperature for 10 h, then was cooled to 0 °C where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (30 mL). The mixture was extracted with four 15-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (20 -t 30%) afforded alcohol 58 as a white solid (500 mg, 92%): mp 30-31 °C. High resolution 1H NMR analysis (400 MHz, CDC13) of the corresponding Mosher ester derivative,58 prepared as described above for alcohol 50, established that alcohol 58 was of;:;:95% ee. 181 1 H NMR (300 MHz, CDC4) 0: 7.15-7.35 (m, 5H, aromatic), 3.61 (m, 2H, HOCH 2 ), 2.89 (dd, 1H, 1 1 = 13.6 Hz, 12 = 3.3 Hz, one of PhCH2 ), 2.47 (dd, 1H, 11 = 13.6 Hz, 12 = 10.9 Hz, one of PhCH 2), 1.54 (m, 1H, HOCH 2 CH), 1.02 (s, 9H, C(CH3 ) 3). 13 C NMR (7 5 MHz, CDCl~ 8: 142.2, 129.0, 128.4, 125.8, 62.7, 53.0, 34.0, 33.0, 28.4. FTIR (neat, cm-1): 3385 (br, m, OH). HRMS (EI): Calcd for C 13 H 20 0 (Mt: 192.1514. Found: 192.1513. TLC (50% EtOAc-hexanes), R; 58: 0.60 (UV, PMA). 23: 0.50 (UV, PMA). 182 H3q CH 3 THF, 66 oc 5"/o HO~CH3 CHzC6Hs 58 (S)-!3:Cl. 1-Dimethylethyl)benzenepropanol 5 8 Alcohol 58 was prepared by the reduction of amide 23 with LPT, as described above for the alcohol 50. Thus, treatment of amide 23 (100 mg, 0.283 mmol, 1 equiv) with LPT (1.13 mmol, 4.00 equiv) at 66 OC for 12 h afforded alcohol 58 as a colorless liquid (2.9 mg, 5%) after purification by flash column chromatography (gradient elution of ether-petroleum ether, 15---* 30%). Spectroscopic data were identical to those listed above. TLC (50% EtOAc-hexanes), R1: 58: 0.60 (UV, PMA). 23: 0.50 (UV, PMA). 183 ~ ~H30 ~~~CH3 THF, 23 oc 27 78% OH CH3 CH3 CH3 UH2NBH3 1 3 4 6 HO~~H3 CH3 CH3 2 5 59 (2R. 4S)-2.4-Dimethylhexanol 59 A solution of n-butyllithium in hexanes (2.44 M, 5.51 mL, 13.4 mmol, 3.90 equiv) was added to a solution of diisopropylamine (2.03 mL, 14.5 mmol, 4.20 equiv) in tetrahydrofuran (10 mL) at-78 °C. The resulting solution was stirred at -78 °C for 10 min, then was warmed to 0 CC and was held at that temperature for 10 min. Borane-ammonia complex (90%, 473 mg, 13.8 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 °C. After 20 min, the suspension was cooled to 0 °C. A solution of amide 27 (1.00 g, 3.45 mmol, 1 equiv) in tetrahydrofuran (4 mL, followed by a 4-mL rinse) was added via cannula. The reaction mixture was warmed to 23 °C and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (40 mL). Volatile organic solvents were removed by rotary evaporation, and the resulting aqueous solution was extracted with three 20-mL portions of ether. The combined ether fractions were washed sequentially with 3 N aqueous hydrochloric acid solution (5 mL), 2 N aqueous sodium hydroxide solution (5 mL), and brine (5 mL). The organic layer was dried over magnesium sulfate and was concentrated. Purification of the residue by flash column chromatography (40% ether-petroleum ether) afforded alcohol 59 as a colorless liquid (350 mg, 78%). Acetylation of alcohol 59 (25 mg, 0.19 mmol, 1 equiv) with acetic anhydride (45 Jl.L, 0.48 mmol, 2.5 equiv) and 4dimethylaminopyridine (59 mg, 0.48 mmol, 2.5 equiv) in dichloromethane (1 mL) at 23 CC for 1 h and chiral capillary GC analysis59 of the resulting acetate ester established that alcohol 59 was of 97% de. 184 1 H NMR (400 MHz, CDC13) 0: 3.48 (dd, 1H, 11 = 10.3 Hz, 12 = 5.9 Hz, one of HOCH2 ), 3.40 (dd, 1H, 11 = 10.3 Hz, 12 = 6.6 Hz, one of HOCH 2 ), 1.72 (m, 1H, H1), 1.42 (m, 1H, H4), 1.32 (m, 1H, one of H3), 1.18 (m, 1H, one of H3), 1.12 (m, 2H, H6), 0.89 (d, 3H, J = 6.6 Hz, H2), 0.87 (t, 3H, J = 7.3 Hz, H7), 0.84 (d, 3H, J = 6.2 Hz, H5). 13 C NMR (100 MHz, CDCI~ o: 68.9, 40.2, 33.2, 31.5, 30.4, 18.8, 16.3, 11.3. FTIR (neat, cm-1): 3331 (s, br, OH). HRMS (EI): Calcd for C 8H 16 (M-H2 0t: 112.1252. Found: 112.1251. TLC (50% EtOAc-hexanes), R; 59: 0.54 (PMA). 27: 0.41 (UV, PMA). 185 Qx30 ~CH3 .,ij . :: I OH CH3 CH3 CH3 ::: ::: 28 1 THF, 23 oc 3 6 HO~CH3 - - CH3 CH3 2 79% 4 7 5 60 C2S.4S)-2.4-Dimethylhexanol 60 . A solution of n-butyllithium in hexanes (2.44 M, 5.53 mL, 13.5 mmol, 3.90 equiv) was added to a solution of diisopropylamine ((2.04 mL, 14.6 mmol, 4.20 equiv) in tetrahydrofuran (10 mL) at-78 °C. The resulting solution was stirred at -78 °C for 10 min, then was warmed to 0 CC and was held at that temperature for 10 min. Borane-ammonia complex (90%, 475 mg, 13.8 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 °C. After 20 min, the suspension was cooled to 0 °C. A solution of amide 28 (1.01 g, 3.46 mmol, 1 equiv) in tetrahydrofuran (4 mL, followed by a 4-mL rinse) was added via cannula. The reaction mixture was warmed to 23 °C and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (40 mL). After an aqueous work-up using the procedure described above for alcohol 59, purification of the product by flash column chromatography (40% ether-petroleum ether) afforded alcohol 60 as a colorless liquid (357 mg, 79%). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as described above for alcohol 59, established that alcohol60 was of 98% de. 186 H NMR (400 MHz, CDClJ o: 1 3.53 (dd, 1H, J 1 = 10.3 Hz, J 2 = 5.1 Hz, one of HOCH2 ), 3.38 (dd, 1H, J 1 = 10.3 Hz, J 2 = 7.0 Hz, one of HOCH2), 1.72 (sx, 1H, J = 6.6 Hz, H1), 1.40-1.50 (m, 4H, H3, H4, one of H6), 1.09 (m, 1H, one of H6), 0.92 (d, 3H, J = 7.0 Hz, H2), 0.87 (d, 3H, J = 6.2 Hz, H5), 0.86 (t, 3H, J = 7.3 Hz, H7). HRMS (EI): Calcd for C8H 16 (M-H20t: 112.1252. Found: 112.1249. 13 C NMR (1 00 MHz, CDClJ 8: 68.2, 40.6, 33.1, 31.5, 28.9, 19.7, 17.2, 11.1. FTIR (neat, cm-1): 3332 (s, br, OH). TLC (60% EtOAc-hexanes), R; 60: 0.59 (PMA). 28: 0.42 (UV, PMA). 187 Oyl~~Ph THF, 23 oc 29 95% OH CH3 CHs CHs LiH2NBHs 1 3 4 HO~Ph CH 3 CHs 2 5 61 C2R.4S)-2.4-Dimethyl-5-pheny1pentano1 61 A solution of n-butyllithium in hexanes (2.33 M, 20.0 mL, 46.5 mmol, 3.90 equiv) was added to a solution of diisopropylamine (7.02 mL, 50.1 mmol, 4.20 equiv) in tetrahydrofuran (50 mL) at -78 °C. The resulting solution was stilTed at -78 °C for 10 min, then was warmed to 0 CC and was held at th<:J.t temperature for 10 min. Borane-ammonia complex (90%, 1.64 g, 47.7 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 oc_ After 15 min, the suspension was cooled to 0 °C. A solution of amide 29 (4.22 g, 11.9 mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was warmed to 23 OC and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (120 mL). The mixture was sti1red for 30 min at 0 CC then was extracted with four 45-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (20 mL), 2 N aqueous sodium hydroxide solution (20 mL), and brine (20 mL). The organic layer was dried over magnesium sulfate and was concentrated. Purification of the residue by flash column chromatography (35% ether-petroleum ether) afforded alcohol 61 as a colorless liquid (2.18 g, 95%). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as describ~d above for alcohol 59, established that alcohol61 was of 98% de. 188 7.1-7.4 (m, 5H, aromatic), 3.52 (dd, lH, 1 1 = 10.5 Hz, 12 = 5.1 Hz, one of HOCH 2), 3.38 (dd, lH, 1 1 = 10.5 Hz, 12 = 6.6 Hz, one of HOCH 2), 2.68 (dd, 1H, 1 1 = 13.3 Hz, 12 = 5.4 Hz, one of PhCH 2 ), 2.28 (dd, 1H, 11 = 13.3 Hz, 12 = 8.6 Hz, one of PhCH2), 1.80 (m, 2H, Hl, H4), 1.37 (dd, lH, 11 = 13.7 Hz, 12 = 6.8 Hz, one of H3), 1.03 (dd, lH, 1 1 = 13.7 Hz, 12 = 7.3 Hz, one of H3), 0.96 (d, 3H, 1 = 6.7 Hz, H2), 0.86 (d, 3H, 1 = 6.6 Hz, H5). 13 C NMR (100 MHz, CDCl:J 8: 141.4, 129.2, 128.2, 125.8, 68.2, 43.4, 40.8, 33.3, 32.5, 20.2, 17 .4. FTIR (neat, cm-1): 3346 (br, m, OH). Analysis: Calcd for C 13H 20 0: C, 81.20; H, 10.48; N, 0. Found: C, 80.93; H, 10.43; N, <0.05. 1LC (60% EtOAc-hexanes), R; 61: 0.64 (UV, PMA). 29: 0.51 (UV, PMA). 189 ~30 .o = t;J~CH3 OH CH3 CH3 CH3 LiH 2 NBH3 THF, 23 oc 30 1 3 CH3 CH3 2 96% 4 HO~Ph 5 62 C2S.4S)-2.4-Dimethyl-5-phenylpentanol 6 2 A solution of n-butyllithium in hexanes (2.33 M, 18.9 mL, 44.1 mmol, 3.90 equiv) was added to a solution of diisopropylamine (6.66 mL, 47.5 mmol, 4.20 equiv) in tetrahydrofuran (50 rnL) at -78 °C. The resulting solution was stitTed at -78 °C for 10 min, then was warmed to 0 CC and was held at that temperature for 10 min. Borane-ammonia complex (90%, 1.55 g, 45.3 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 °C. After 15 min, the suspension was cooled to 0 °C. A solution of amide 30 (4.00 g, 11.3 mmol, 1 equiv) in tetrahydrofuran (30 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was warmed to 23 OC and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (120 mL). After an aqueous work-up using the procedure described above for alcohol 61, pmification of the product by flash column chromatography (35% ether-petroleum ether) afforded alcohol 62 as a colorless liquid (2.10 g, 96%). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as described above for alcohol 59, established that alcohol62 was of 98% de. 190 7.0-7.2 (m, 5H, aromatic), 3.13 (m, 2H, HOCH 2), 2.48 (dd, 1H, 1 1 = 13.2 Hz, 12 = 6.1 Hz, one of PhCH2 ), 2.27 (dd, lH, 1 1 = 13.2 Hz, 12 = 7.9 Hz, one of PhCH2 ), 1.75 (m, 1H, H1), 1.52 (m, 1H, H4), 1.11 (m, lH, one of H3), 0.99 (m, 1H, one of H3); 0.77 (d, 3H, 1 = 6.6 Hz, H2) , 0.73 (d, 3H, 1 = 6.6 Hz, H5). 13 C NMR (100 MHz, CDClg) 8: 141.4, 129.2, 128.2, 125.8, 69.1, 44.6, 40.3, 33.3, 32.2, 19.2, 16.2. FTIR (neat, cm-1): 3346 (br, m, OH). Analysis: Calcd for C 13H 20 0: C, 8 1.20; H, 10.48; N, 0. Found: C, 81.05; H, 10.53; N, <0.05. 1LC (60% EtOAc-hexanes), R; 62: 0.58 (UV, PMA). 30: 0.41 (UV, PMA). 191 o;;~Ph THF, 23 oc 31 93% OH CH3 CH3 CHa CHa 1 3 4 6 7 HO~Ph CHa CHa CHa 2 5 8 63 (2R AR. 6S2-2.4.6-Trimethyl-7 -pheny1heptano1 6 3 A solution of n-butyllithium in hexanes (2.43 M, 3.54 mL, 8.60 mmol, 3.90 equiv) was added to a solution of diisopropylamine (1.30 mL, 9.28 mmol, 4.20 equiv) in tetrahydrofuran (7.5 mL) at -78 °C. The resulting solution was stirred at -78 CC for 10 min, then was wanned to 0 CC and was held at that temperature for 10 min. Boraneammonia complex (90%, 303 mg, 8.82 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 °C. After 15 min, the suspension was cooled to 0 °C. A solution of amide 31 (0.872 g, 2.21 mmol, 1 equiv) in tetrahydrofuran (7.5 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was wanned to 23 CC and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (30 mL). The mixture was extracted with four 15-mL portions of ether. The combined organic extracts were washed sequentially with 3 N aqueous hydrochloric acid solution (7 mL), 2 N aqueous sodium hydroxide solution (7 mL), and brine (7 mL). The organic layer was dried over magnesium sulfate and was concentrated. Purification of the residue by flash column chromatography using silica gel packed with 35:63:2 ether-petroleum ether-triethylamine and eluted with 35% etherpetroleum ether afforded alcohol63 as a colorless liquid (480 mg, 93%). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as described above for alcohol 59, established that alcohol63 was of 99% de. 192 1 H NMR (400 MHz, CDClJ 8: 7.1-7.4 (m, 5H, aromatic), 3.52 (dd, 1H, 1 1 = 10.5 Hz, 12 = 5.1 Hz, one of HOCH 2 ), 3.37 (dd, 1H, 1 1 = 10.5 Hz, 12 = 6.6 Hz, one of HOCH2), 2.70 (dd, 1H, 1 1 = 13.2 Hz, 12 = 5.1 Hz, one of PhCH 2), 2.23 (dd, 1H, 1 1 = 13.2 Hz, 12 = 8.8 Hz, one of PhCH2 ), 1.81 (m, 1H, Hl), 1.60-1.74 (m, 2H, H7, H4), 1.23-1.33 (m, 2H, H3), 0.88-1.14 (m, 2H, H6), 0.92 (d, 3H, 1 = 6.6 Hz, H2), 0.91 (d, 3H, 1 = 6.2 Hz, H5), 0.81 (d, 3H, 1 = 6.6 Hz, H8). 13 C NMR (100 MHz, CDC13) 8: 141.4, 129.1, 128.0, 125.5, 68.8, 45.3, 44.3, 41.4, 33.1, 32.2, 27.2, 19.3, 19.0, 16.4. FTIR (neat, cm-1): 3331 (br, m, OH). Analysis: Calcd for C 16H 26 0: C, 81.99; H, 11.18; N, 0. Found: C, 81.85; H, 11.35; N, <0.05. TLC (40% EtOAc-hexanes), R; 63: 0.55 (UV, PMA). 31: 0.33 (UV, PMA). tertiary amine by-product 0.46 (UV, PMA). 193 QxaO .0 = OH ~~Ph THF, 23 oc CH3 CH3 CH3 CHa 32 1 4 6 7 CHa CHa CHa 2 93% 3 HO~Ph 5 8 64 C2S. 4R, 6S)-2.4.6-Trimethyl-7 -phenylheptanol 6 4 A solution ofn-butyllithium in hexanes (2.43 M, 3.61 mL, 8.77 mmol, 3.90 equiv) was added to a solution of diisopropylamine (1.32 mL, 9.44 mmol, 4.20 equiv) in tetrahydrofuran (7.5 mL) at -78 °C. The resulting solution was stirred at -78 OC for 10 min, then was warmed to 0 OC and was held at that temperature for 10 min. Boraneammonia complex (90%, 308 mg, 8.99 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 OC for 15 min, then was warmed to 23 °C. After 15 min, the suspension was cooled to 0 °C. A solution of amide 32 (889 mg, 2.25 mmol, 1 equiv) in tetrahydrofuran (7.5 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was warmed to 23 OC and was held at that temperature for 2 h, then was cooled to 0 OC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (30 mL). After an aqueous work-up using the procedure described above for alcohol 63, purification of the product by flash column chromatography using silica gel packed with 38:60:2 ether-petroleum ether-triethylamine and eluted with 38% ether-petroleum ether afforded alcohol 64 as a colorless liquid (488 mg, 93% ). Chiral capillary GC analysis 59 of the corresponding acetate ester, prepared as described above for alcohol 59, established that alcohol 64 was of 97% de. 194 1 H NMR (400 MHz, CDCIJ S: 7.1-7.4 (m, 5H, aromatic), 3.43 (dd, 1H, 1 1 = 10.5 Hz, 12 = 5.9 Hz, one of HOCH2 ), 3.37 (dd, 1H, 11 = 10.5 Hz, 12 = 6~6 Hz, one of HOCH2); 2.65 (dd, 1H, 1 1 = 13.2 Hz, 12 = 5.5 Hz, one of PhCH 2), 2.28 (dd, 1H, 1 1 = 13.2 Hz, 12 = 8.8 Hz, one of PhCH2 ), 1.82 (m, 1H, H1), 1.55-1.75 (m, 2H, H7, H4), 1.25 (m, 1H, one of H3), 1.00-1.12 (m, 3H, one of H3, H6), 0.87 (d, 3H, J = 7.0 Hz, H2), 0.86 (d, 3H, J = 6.6 Hz, H5), 0.81 (d, 3H, J = 6.6 Hz, H8). C NM~ (100 MHz, CDClg) S: 13 141.4, 129.1, 128.0, 125.5, 69.1, 45.7, 43.7, 40.1, 33.1, 32.2, 27.2, 20.0, 19.8, 16.1. FTIR (neat, cm-1): 3332 (br, m, OH). Analysis: Calcd for C16H 26 0: C, 81.99; H, 11.18; N, 0. Found: C, 81.74; H, 11.34; N, <0.05. TLC (40% EtOAc-hexanes), R; 64: 0.53 (UV, PMA). 32: 0.33 (UV, PMA). tertiary amine by-product: 0.43 (UV, PMA). 195 n'1 <?H 3 0 ~~~Ph OH CHs CH CHs CHs THF, 23 oc 33 91% 3 1 3 4 6 7 HO~Ph CH3 CH3 CHs 2 5 8 65 (2R, 4S. 6S)-2.4.6-Trimethyl-7 -phenylheptanol 6 5 A solution of n-butyllithium in hexanes (2.43 M, 3.49 mL, 8.49 mmol, 3.90 equiv) was added to a solution of diisopropylamine (1.28 mL, 9.14 mmol, 4.20 equiv) in tetrahydrofuran (7.5 mL) at -78 oc. The resulting solution was stirred at -78 CC for 10 min, then was warmed to 0 CC and was held at that temperature for 10 min. Boraneammonia complex (90%, 299 mg, 8.71 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 CC for 15 min, then was warmed to 23 °C. After 15 min, the suspension was cooled to 0 °C. A solution of amide 33 (861 mg, 2.18 mmol, 1 equiv) in tetrahydrofuran (7.5 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was warmed to 23 CC and was held at that temperature for 2 h, then was cooled to 0 CC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (30 mL). After an aqueous work-up using the procedure described above for alcohol 63, purification of the product by flash column chromatography using silica gel packed with 35:63:2 ether-petroleum ether-triethylamine and eluted with 35% ether-petroleum ether afforded alcohol 65 as a colorless liquid (463 mg, 91 %). Chiral capillary GC analysis59 of the corresponding acetate ester, prepared as described above for alcohol 59, established that alcohol 65 was of 97% de. 196 H NMR (400 MHz, CDCl~ 8: 1 7.1-7.4 (m, 5H, aromatic), 3.48 (dd, 1H, 1 1 = 12.0 Hz, 1 2 = 6.2 Hz, one of HOCH 2), 3.42 (dd, 1H, 1 1 = 12.0 Hz, 12 = 6.6 Hz, one of HOCH 2), 2.59 (dd, 1H, 11 = 13.4 Hz, 12 = 6.2 Hz, one of PhCH2 ), 2.36 (dd, 1H, 1 1 = 13.4 Hz, 12 = 8.1 Hz, one of PhCH2 ), 1.84 (m, 1H, H1), 1.72 (m, lH, H7), 1.61 (m, 1H, H4), 1.24 (m, lH, one of H3), 1.021.18 (m, 3H, one of H3, H6), 0.90 (d, 3H, J = 6.6 Hz, H2), 0.82 (d, 3H, 1 = 6.6 Hz, H5), 0.79 (d, 3H, 1 = 6.6 Hz, H8). 13 C NMR (1 00 MHz, CDC13) 8: 141.4,_ 129.1, 128.0, 125.5, 68.8, 45.3, 44.3, 41.4, 33.1, 32.2, 27.2, 19.2, 19.0, 16.3. FTIR (neat, cm-1): 3332 (br, m, OH). Analysis: Calcd for C16H 26 0: C, 81.99; H, 11.18; N, 0. Found: C, 82.03; H, 11.23; N, <0.05. TLC (50% EtOAc-hexanes), R; 65: 0.58 (UV, PMA). 33: 0.40 (UV, PMA). tertiary amine by-product: 0.49 (UV, PMA). 197 ~30 .o = OH ~~Ph THF, 23 oc LiH2NBH3 CH3 CH3 CH3 CHa 34 1 4 6 7 HO~Ph CH3 CHa CHa 2 89% 3 5 8 66 (2SAS. 6S)-2.4.6-Trimethyl-7-phenylheptano1 6 6 A solution of n-butyllithium in hexanes (2.43 M, 3.58 mL, 8.70 mmol, 3.90 equiv) was added to a solution of diisopropylamine (1.31 mL, 9.35 mmol, 4.20 equiv) in tetrahydrofuran (7.5 mL) at -78 °C. The resulting solution was stirred at -78 OC for 10 min, then was warmed to 0 OC and was held at that temperature for 10 min. Boraneammonia complex (90%, 303 mg, 8.82 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 OC for 15 min, then was wanned to 23 °C. Mter 15 min, the suspension was cooled to 0 °C. A solution of amide 34 (872 mg, 2.21 mmol, 1 equiv) in tetrahydrofuran (7 .5 mL, followed by a 5-mL rinse) was added via cannula over 3 min. The reaction mixture was warmed to 23 OC and was held at that temperature for 2 h, then was cooled to 0 OC where excess hydride was quenched by the careful addition of 3 N aqueous hydrochloric acid solution (30 mL). Mter an aqueous work-up using the procedure described above for alcohol 63, purification of the product by flash column chromatography using silica gel packed with 35:63:2 ether-petroleum ether-triethylamine and eluted with 35% ether-petroleum ether afforded alcohol 66 as a colorless liquid (467 mg, 89% ). Chiral capillary GC analysis59 of the con·esponding acetate ester, prepared as described above for alcohol 59, established that alcohol 66 was of 99% de. 198 1 H NMR (400 MHz, CDClJ 8: 7.1-7.4 (m, 5H, aromatic), 3.51 (dd, 1H, 11 = 11.7 Hz, 12 = 5.1 Hz, one of HOCH 2 ), 3.38 (dd, 1H, 1 1 = 11.7 Hz, 12 = 7.0 Hz, one of HOCH 2), 2.56 (dd, 1H, 1 1 = 13.2 Hz, 12 = 6.2 Hz, one of PhCH2), 2.39 (dd, 1H, 1 1 = 13.2 Hz, 12 = 8.1 Hz, one of PhCH2 ), 1.82 (m, 1H, H1), 1.73 (m, 1H, H7), 1.61 (m, 1H, H4), 1.24 (m, 1H, one of H3), 1.13 (m, 1H, one of H3), 1.06 (m, 1H, one of H6), 0.98 (m, 1H, one of H6), 0.91 (d, 3H, 1 = 6.6 Hz, H2), 0.83 (d, 3H, 1 = 7.3 Hz, H5), 0.82 (d, 3H, 1 = 7.5 Hz, H8). 13 C NMR (100 MHz, CDC13) 8: 141.5, 129.1, 128.0, 125.6, 68.4, 44.7, 44.0, 41.8, 33.0, 32.3, 27.4, 20.1, 19.1, 17.1. FI1R (neat, cm-1): 3345 (br, m, OH). Analysis: Calcd for C 16H 26 0: C, 81.99; H, 11.18; N, 0. Found: C, 81.71; H, 11.39; N, <0.05. TLC (40% EtOAc-hexanes), R; 66: 0.55 (UV, PMA). 34: 0.34 (UV, PMA). tertiary amine by-product: 0.45 (UV, PMA). 199 HO~Ph CH3 PPh3 , 12 , imidazole I~ Ph CH 2 CI2 , 23 oc CH3 50 98% 67 (R)-1-Iodo-2-methyl~3-phenylpropane 67 Imidazole (6.86 g, 101 mmol, 1.50 equiv) and iodine (23.0 g, 90.7 mmol, 1.35 equiv) were added sequentially to a solution of triphenylphosphine (21.1 g, 80.6 mmol, 1.20 equiv) in dichloromethane (250 mL) at 23 °C. A solution of alcohol 50 (10.1 g, 67.2 mmol, 1 equiv) in dichloromethane (30 mL) was added to the resulting fine suspension via cannula. After 2 h, dichloromethane was removed in vacuo. The solid residue was suspended in a minimal amount of dichloromethane (30 mL), and the suspension was loaded onto a column of silica gel eluting with 10% ether-petroleum ether to afford the iodide 67 as a colorless liquid (17.1 g, 98%). 200 6.9-7.2 (m, 5H, aromatic), 2.73 (dd, lH, J 1 = 9.7 Hz, J 2 = 4.9 Hz, one of ICH2 ), 2.70 (dd, 1H, J 1 = 9.7 Hz, J 2 = 5.5 Hz, one ofiCH2), 2.43 (dd, 1H, J 1 = 13.5 Hz, J2 = 7.0 Hz, one of PhCH2), 2.18 (dd, 1H, J 1 = 13.5 Hz, J2 = 7.1 Hz, one of PhCH2), 1.33 (m, 1H, CH 3 CH), 0.72 (d, 3H, J = 6.8 Hz, CH 3 ). 13 C NMR (100 MHz, CDC13) 8: 140.8, 129.0, 128.3, 126.2, 42.5, 36.7, 20.7, 17.0. FTIR (neat, cm-1): 2958 (s), 1494 (s), 1453 (s), 1194 (s). HRMS (EI): Calcd for C 10H 13I (Mt: 260.0062. Found: 260.0057. Analysis: Calcd for C10H 13I: C, 46.18; H, 5.04. Found: C, 46.34, H, 5.20. TLC (40% EtOAc-hexanes), R; 67: 0.69 (UV, PMA). 50: 0.38 (UV, PMA). 201 HO---y-y--Ph CH 3 CHs 61 PPh:3, ~.imidazole I~ Ph CH:2CI 2 , 23 oc CH3 CHs 96% 68 (2R .4S)-1-Iodo-2.4-dimethyl-5-phenylpentane 6 8 Imidazole (1.08 g, 15.8 mmol, 1.60 equiv) and iodine (3.51 g, 13.8 mmol, 1.40 equiv) were added sequentially to a solution of triphenylphosphine (3.11 g, 11.9 mmol, 1.20 equiv) in dichloromethane (50 mL) at 23 oc_ A solution of alcohol 61 (1.90 g, 9.88 mmol, 1 equiv) in dichloromethane (5 mL, followed by a 4-mL rinse) was added to the resulting fme suspension via cannula. After 4 h, dichloromethane was removed in vacuo. The solid residue was suspended in a minimal amount of dichloromethane (5 mL), and the suspension was loaded onto a column of silica gel eluting with 10% ether-petroleum ether. The combined fractions containing the iodide 68 were washed with saturated aqueous sodium thiosulfate solution (10 mL), then were dried over sodium sulfate and were concentrated to afford the iodide 68 as a clear red liquid (2.87 g, 96%). 202 1 H NMR (400 MHz, CDC1:J 8: 7.1-7.4 (m, 5H, aromatic), 3.24 (dd, lH, 11 = 9.6 Hz, 12 = 4.0 Hz, one of ICH 2 ), 3.11 (dd, 1H, 1 1 = 9.6 Hz, 12 = 6.0 Hz, one of ICH2 ), 2.66 (dd, 1H, 1 1 = 13.3 Hz, 12 = 5.7 Hz, one of PhCH2), 2.32 (dd, 1H, 1 1 = 13.3 Hz, 12 = 8.5 Hz, one of PhCH 2), 1.77 (m, lH, ICH2 CH), 1.54 (m, 1H, PhCH2 CH), 1.37 (m, 1H, one of PhCH 2CHCH 2), 1.10 (m, 1H, one of PhCH 2CHCH2 ), 0.99 (d, 3H, J = 6.5 Hz, ICH2 CHCH 3), 0.85 (d, 3H, J = 6.6 Hz, PhCH 2CHCH 3). 13 C NMR (100 MHz, CDC13) 8: 140.9, 129.2, 128.1, 125.7, 43.8, 43.5, 32.3, 31.9, 21.4, 19.5, 17.7. FTIR (neat, cm-1): 2957 (s), 1494 (s), 1454 (s). HRMS (FAB): Calcd for C 13H 19I (Mt: 302.0533. Found: 302.0520. Analysis: Calcd for C13H 19 I: C, 51.67; H, 6.34. Found: C, 51.69, H, 6.44. TLC (40% EtOAc-hexanes), R; 68; 0.74 (UV, PMA). 61: 0.46 (UV, PMA). 203 HO~Ph CH3 CH3 62 PPhs, lz, imidazole I~ Ph CH2 CI 2 , 23 oc CH3 CH3 97% 69 C2S.4S)-1-Iodo-2.4-dimethyl-5-phenylpentane 6 9 Imidazole (975 mg, 14.3 mmol, 1.45 equiv) and iodine (3.26 g, 12.8 mmol, 1.30 equiv) were added sequentially to a solution of triphenylphosphine (2.98 g, 11.4 mmol, 1.15 equiv) in dichloromethane (50 mL) at 23 °C. A solution of alcohol 62 (1.90 g, 9.88 mmol, 1 equiv) in dichloromethane (5 mL, followed by two 2.5-mL rinses) was added to the resulting fine suspension via cannula. Mter 3.2 h, dichloromethane was removed in vacuo. The solid residue was suspended in a minimal amount of dichloromethane (5 mL), and the suspension was loaded onto a column of silica gel eluting with 10% etherpetroleum ether. The combined fractions containing the iodide 69 were washed with saturated aqueous sodium thiosulfate solution (10 mL), then were d1ied over sodium sulfate and were concentrated to afford the iodide 69 as a clear red liquid (2.90 g, 97% ). 204 H NMR (400 MHz, CDC13) o: 1 7.1-7.4 (m, 5H, aromatic), 3.19 (dd, 1H, 1 1 = 9.5 Hz, 12 = 5.1 Hz, one of CH2I), 3.12 (dd, 1H, 1 1 = 9.5 Hz, 12 = 6.2 Hz, one of CH2I), 2.61 (dd, 1H, 11 = 13.4. Hz, 12 = 6.1 Hz, one of PhCH2), 2.40 (dd, 1H, 1 1 = 13.4 Hz, 12 = 8.1 Hz, one of PhCH 2), 1.78 (m, 1H, IC~CH), 1.62 (m, 1H, PhCH2 CH), 1.20-1.27 (m, 2H, PhCH2 CHCH 2), 0.93 (d, 3H, 1 = 6.5 Hz, ICH2 CHCH3), 0.84 (d, 3H, 1 = 6.6 Hz, PhCH 2 CHCH 3). C NMR (1 00 MHz, CDC13) o: 13 141.0, 129.1, 128.1, 125.7, 44.1, 43.8, 32.54, 32.45, 20.1, 19.2, 18.1. 2979 (s), 2957 (s), 2918 (s), 1494 (s), 1454 (s), 1378 (s); 742 (s). HRMS (FAB): Calcd for C13 H20 I (MHt: 303.0610. Found: 303.0601. Analysis: Calcd for C 13H 19I: C, 51.67; H, 6.34. Found: C, 51.67, H, 6.46. TLC (40% EtOAc-hexanes), R; 69: 0.77 (UV, PMA). 62: 0.51 (UV, PMA). 205 CH 3 (CH2) 10 COCI CH 3 (C~) 10 CONEt 2 70 98% N ,N-Diethyldodecanamide 7 0 Diethylamine (5.30 mL, 51.3 mmol, 2.50 equiv) was added quickly in 1-mL portions to a well-stirred solution of dodecanoyl chloride (4.49 g, 20.5 mmol, 1 equiv) in dichloromethane (120 mL) at 23 °C. After stirring for 10 h at 23 °C, the reaction mixture was diluted with dichloromethane (300 mL), and the solution was extracted sequentially with 1 N aqueous sodium hydroxide solution (2 x 50 mL) and 1 N aqueous hydrochloric acid solution (2 x 50 mL). The organic layer was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (40% ethyl acetate-hexanes) afforded amide 70 as a colorless oil (5.15 g, 98%). 3.27-3.41 (m, 4H, NCH 2 CH 3), 2.28 (t, 2H, J = 7.7 Hz, CH 2CO), 1.26-1.84 [m, 18H, (CH 2) 9 CH2 CO], 1.17 (t, 3H, J = 7.1 Hz, one of NCH 2 CH 3 ), 1.11 (t, 3H, J = 7.1 Hz, one of NCH2 CH3), 0.88 [t, 3H, J = 6.6 Hz, CH3 (CH2 ) 9 ]. 2924 (s), 2853 (m), 1644 (s, C=O), 1462 (m), 1427 (m). HRMS (FAB): Calcd for C 16H 34NO (MH)+: 256.2640. Found: 256.2644. TLC (50% EtOAc-hexanes) R; 70: 0.45 (PMA}. 206 CH 3 (CH~1 0 CON(f·Pr)2 CH2CI2, 23 oc 71 89% N,N-Diisopropyldodecanamide 71 Diisopropylamine (7.22 mL, 51.5 mmol, 2.50 equiv) was added quickly in 1-mL portions to a well-stirred solution of dodecanoyl chlmide (4.51 g, 20.6 mmol, 1 equiv) in dichloromethane (100 mL) at 23 °C. After stirring for 10 hat 23 °C, the reaction mixture was diluted with dichloromethane (300 mL), and the mixture was extracted successively with 1 N aqueous sodium hydroxide solution (2 x 50 mL) and 1 N aqueous hydrochloric acid solution (2 x 50 mL). The organic layer was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (15% ethyl acetate-hexanes) afforded amide 71 as a colorless oil (5.16 g, 89%). 3.97 (sp, 1H, 1 = 6.7 Hz, one of NCH, 3.47 (br, 1H, one of NCH), 2.27 (t, 2H, 1 = 7.7 Hz, CH2 CO), 1.36-1.81 [m, 18H, (CH2) 9 CH2 CO], 1.27 [d, 6H, 1 = 10.6 Hz, one of CH(CH 3) 2], 1.19 [d, 6H, 1 = 6.7 Hz, one of CH(CH 3) 2], 0.88 (t, 3H, 1 = 6.6 Hz, CH3 CH2 ). FI1R (neat, cm-1): 3002 (m), 2962 (s), 2925 (s), 2854 (s), 1646 (s), 1463 (m), 1440 (m), 1369 (m), 1336 (m), 1304 (m), 1216 (m), 1135 (m), 1044 (m). HRMS (FAB) Calcd for C 18H 38NO (MHt: 284.2953. Found: 284.953. TLC (50% EtOAc-hexanes) R; 71: 0.66 (PMA). 207 COCI iG Et 2NH, DMAP C~CI2, 23 oc Ii~ 1 92% 2 72 1-Adamantanecarboxylic Acid N .N-Diethylamide 7 2 Diethylamine (1.55 mL, 15.0 mmol, 3.00 equiv) was added to a well-stirred solution of 1-adamantanecarbonyl chloride (0.990 g, 4.98 mmol, 1 equiv) and 4dimethylaminopyridine (18.0 mg, 0.149 mmol, 0.03 equiv) in dichloromethane (20 mL) at 0 °C. The reaction mixture was warmed to 23 °C and held at that temperature for 2.5 h. Excess anhydride was quenched by the addition of 0.5 N aqueous sodium hydroxide solution (10 mL). The mixture was diluted with dichloromethane (200 mL) and the resulting mixture was extracted sequentially with 0.5 N aqueous sodium hydroxide solution (3 x 25 mL) and 3 N aqueous hydrochloric acid solution (3 x 25 mL). The organic layer was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (32% ethyl acetate-hexanes) afforded amide 72 as a white solid (1.07 g, 92%): mp: 61-63 °C. 1 H NMR (300 MHz, CDC13) 8: 208 3.42 (m, 4H, NC;H 2 CH 3),, 2.04 (s, 3H, H1), 2.00 (s,• 6H, H3), 1.72 It(s, 6H, :GJ2), 1.13 (t, 6H, J = 7.6 , I ! ' ' Hz, NCH2 CH 3). . 2970 (m), 2904 (s~, 2850 (fU), 1621 (s, C=O), 1614 I (s, C=O), 1454 (m), 1446 (m), 1409 (m), 1282 (m), 1250 (m), 1061 (m). HRMS (FAB) . Calcd for C15H 26NO (MHyf·: 236.2014. Found: 236.2007. TLC (50% EtOAc-hexanes) R; 72: 0.51 (PMA). 1-adamantanecarb:oxylic acid: 0.38 (PMA). COCI JiJ (i-Pr)2NH, DMAP THF, 66 oc 67% f/Prj, 1 209 2 73 1-Adamantanecarboxylic Acid N.N-Diisopropylamide 7 3 Diisopropylamine (1.58 mL, 11.3 mmol, 3.00 equiv) was added to a solution of 1adamantanecarbonyl chloride (750 mg, 3.78 mmol, 1 equiv) and 4-dimethylaminopyridine (14 mg, 0.11 mmol, 0.03 equiv) in tetrahydrofuran (9 mL) at 23 °C. The mixture was heated to reflux and held at that state for 24 h. The reaction mixture was cooled to 23 °C, and unreacted acid chloride was quenched by the addition of 1 N aqueous sodium hydroxide solution (5 mL). The mixture was partitioned between dichloromethane (150 mL) and 1 N aqueous sodium hydroxide solution (50 mL). The organic layer was separated and extracted with 3 N aqueous hydrochloric acid solution (3 x 25 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (10% ethyl acetate-hexanes) afforded amide 73 as a white solid (666 mg;67%): mp 149-152 °C. 210 4.54 [br, s, LEl, CH(Cfl 3 ) 2 ], 3.24 [br, s, 1H, CH(CH3 ) 2 ], 2.0~ (s, 3H,; H1), 1.98 (s, 6H, H3), 1.71 (s, . 6H, H2), 1.39; (br, s, 6H, two CH3 groups), 1.20 (br, s, 6H, ~wo CH 3 groups). 2961 (m), 2910 (m), 28i48 (m), 1609 (s, C=O), I : 1438 (m), 1369 Cm), 132~'(m), 1301 (m), 1210 (m), 1026 (m). HRMS (FAB): . Calcd for C 17H 30 NO (ivfHr: 264.2327. ' I i Found: 264.2328. 1LC (40% EtOAc-hexanes) R; 73: 0.49 (PMA)~ 1-adamantanecarboxylic aoid: 0.35 (PMA). . ; 211 LiH2NBH3 CH3(CH2)10CONEt2 THF, 23 oc CH3(CH2) 1oCH 20H 74 70 84% 1-Dodecanol 7 4 A solution of n-butyllithium in hexanes (2.37 M, 0.681 mL, 1.61 mmol, 4.00 equiv) was added to an ice-cooled suspension of borane-ammonia complex (90%, 0.0580 g, 1.69 mmol, 4.20 equiv) in tetrahydrofuran (1.5 mL). The resulting suspension was warmed briefly to 23 °C, then was cooled to 0 °C. A solution of amide 70 (103 mg, 0.403 mmol, 1 equiv) in tetrahydrofuran (1.5 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was warmed to 23 °C and held at that temperature for 1.3 h. Excess hydride was quenched by the dropwise addition of 1 N aqueous hydrochloric acid solution (3 mL) at 0 °C. The mixture was partitioned between 1 N aqueous hydrochloric acid solution (50 mL) and ether (15 mL). The aqueous layer was separated and extracted with three 15-mL portions of ether. The combined organic extracts were washed with 1 N aqueous hydrochloric acid solution (5 mL) and were concentrated. The residue was stirred in 1 N aqueous sodium hydroxide solution (50 mL) for 20 min, and the mixture was extracted with ether (20 mL). The aqueous layer was separated, then was saturated with sodium chloride and was extracted with ether (2 x 20 mL). The combined ether extracts were washed sequentially with 1 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (30 ~ 40%) afforded alcohol 74 as a low-melting solid (70.7 mg, 94%): mp 24-26 °C. 212 3.62 (t, 3H, J = 6.6 Hz, HOCH 2), 1.58 (m, 2H, HOCH 2CH2 ), 1.25 [m, 18H, (CH 2 ) 9 CH2CH2 0H], 0.86 (m, 3H, CH3). 13 C NMR (7 5 MHz, CDCl:J 8: 63.0, 32.8, 31.9, 29.6, 29.4, 29.3, 25.7, 22.7, 14.1. 3332 (br, m, OH), 2922 (s), 2853 (s), 1464 (m), 1057 (m). TLC (50% EtOAc-hexanes) R; 7 4: 0.53 (PMA). 70: 0.49 (PMA). 213 CH 3 (CH2) 10 CON(l-Pr}2 LiH 2NBHs THF, 23 oc CHs(CH~1 0 CH20H 74 71 68% 1-Dodecanol 7 4 A solution of n-butyllithium in hexanes (2.47 M, 1.84 mL, 4.55 mmol, 4.00 equiv) was added to a suspension ofborane-ammonia complex (90%, 0.160 g, 4.66 mmol, 4.10 equiv) in tetrahydrofuran (5 mL) at 0 °C. The suspension was warmed briefly to 23 °C, then was cooled to 0 °C. A solution of amide 71 (322 mg, 1.14 mmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 1.5-mL rinse) was added via cannula. The reaction mixture was warmed to 23 OC and held at that temperature for 6 h. Excess hydride was quenched at 0 OC by the dropwise addition of 3 N aqueous hydrochloric acid solution (3 mL). The mixture was partitioned between 1 N aqueous hydrochloric acid solution (9 mL) and ether (15 mL). The aqueous layer was separated and extracted with three 15-mL portions of ether. The combined organic extracts were washed with 1 N aqueous hydrochloric acid solution (5 mL) and were concentrated. The residue was stin·ed in 1 N aqueous sodium hydroxide solution (60 mL) for 1 h, and the mixture was extracted with ether (20 mL). The aqueous layer was separated and saturated with sodium chloride, then was extracted with ether (3 x 20 mL). The combined ether extracts were washed sequentially with 1 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over sodium sulfate and were concentrated. Pmification of the residue by flash column chromatography (35:65:2 ether-petroleum ether-triethylamine) afforded alcohol 7 4 as a low-melting solid (143 mg, 68%): mp 24-26 °C. Spectroscopic data were identical to those listed above. 1LC (50% EtOAc-hexanes) R; 7 4: 0.58 (PMA). 71: 0.70 (PMA). tertiary amine by-product: 0.25 (PMA). i)EO 214 LiH2NBH3 THF, 23 oc 87% 72 /J~H 1 2 75 1-Adamantanemethanol7 5 A solution of n-butyllithium in hexanes (2.34 M, 1.41 mL, 3.30 mmol, 3.90 equiv) was added to solution of diisopropylamine (0.498 mL, 3.55 mmol, 4.20 equiv) in tetrahydrofuran (3 mL) at-78 °C. The resulting solution was stirred at -78 CC for 10 min, then was warmed to 0 °C and held at that temperature for 5 min. Borane-ammonia complex (90%, 116 mg, 3.38 mmol, 4.00 equiv) was added in one portion, and the suspension was stirred at 0 °C for 20 min, then was warmed to 23 °C. After 20 min, the suspension was cooled to 0 °C, and a solution of amide 72 (199 mg, 0.845 mmol, 1 equiv) in tetrahydrofuran (3 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was warmed to 23 OC and held at that temperature for 16 h, then excess hydride was quenched by the addition of 3 N aqueous hydrochloric acid solution (10 mL). The mixture was extracted with four 9-mL portions of ether. The combined ether fractions were washed sequentially with 3 N aqueous hydrochloric acid solution (3 mL) and brine (3 mL), then were dried over magnesium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (30--+ 40%) afforded alcohol75 as a crystalline solid (122 mg, 87%): mp 114--115 °C. 215 3.20 (d, 2H, J = 6.2 Hz, CH2 0H), 2.00 (m, 3H, H1), 1.69 (m. 6H, H3), 1.51 (d, 6H, J = 2.3 Hz, H2), 1.24 (t, lH, J = 6.2 Hz, OH). 13 C NMR (75 MHz, CDCIJ o: 73.6, 38.9, 37.1, 34.4, 28.1. FTIR (neat, cm-1) 3216 (br, m, OH), 2896 (s), 2844 (m), 1052 (m). Analysis: Calcd for C 11 H 18 0: C, 79.46; H, 10.91. Found: C, 79.61; H, 10.85. 75: 0.50 (PMA). 72: 0.56 (PMA). 216 ;]j(i-PriJ THF, 66 oc 47% 73 JJ~H 1 2 75 1-Adamantanemethanol7 5 A solution of n-butyllithium in hexanes (2.47 M, 0.970 mL, 2.39 mmol, 4.00 equiv) was added to a suspension ofborane-ammonia complex (90%, 86 mg, 2.51 mmol, 4.20 equiv) in tetrahydrofuran (2 mL) at 0 °C. The resulting suspension was warmed briefly to 23 °C, then was cooled to 0 °C. A solution of the amide 73 (158 mg, 0.598 mmol, 1 equiv) in tetrahydrofuran (1 mL, followed by a 1-mL rinse) was added via cannula. The reaction mixture was heated to reflux and held at that state for 1.7 h. The reaction mixture was cooled to 0 OC and excess hydride was quenched by the dropwise addition of 1 N aqueous hydrochloric acid solution (3 mL). The mixture was partitioned between brine (50 mL) and ether (20 mL). The aqueous layer was separated and extracted with three 20-mL portions of ether. The combined organic extracts were washed with 1 N aqueous hydrochloric acid solution (5 mL), then were concentrated. The residue was stirred in 2 N aqueous sodium hydroxide solution (50 mL) for 30 min, and the mixture was extracted with ether (20 mL). The aqueous layer was separated and saturated with sodium chloride, then was extracted with ether (2 x 20 mL). The combined ether extracts were washed sequentially with 1 N aqueous hydrochloric acid solution (5 mL) and brine (5 mL), then were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ether-petroleum ether (25 -7 40%) afforded alcohol 75 as a white solid (47.2 mg, 47%) with the same melting point and spectroscopic data as those listed above. TLC (40% EtOAc-hexanes) R; 75: 0.42 (PMA). 73: 0.59 (PMA). tertiary amine by-product: 0.71 (PMA). 217 n-Buli THF, 0 --7 23 oc Lithium Amidotrihydroborate Borane-ammonia complex (90%, 9.60 mg, 0.311 mmol, 1 equiv) was suspended in tetrahydrofuran (1 mL). The solution was cooled to 0 °C, and a solution of n- butyllithium in hexanes (2.49 M, 0.125 mL, 0.311 mmol, 1 equiv) was added via syringe. The mixture was stirred at 0 OC for 3 min, at 23 OC for 3 min, then was cooled to 0 °C. Organic solvents were removed under vacuum (0.5 mm Hg) for 1 h, and the residue was suspended in THF-d8 • The cloudy suspension was transferred into an NMR tube. 11 B NMR (32 MHz, THF-d8 , B(OMe) 3 reference) o: -40.5 (LiH2NBH3). 11 B NMR (32 MHz, THF-d8, BF3•0E1i_ reference) 8: -22.2 (LiH2NBH3 ). 218 (CH 3 )sCCH 2 Li THF, 0 -t 23 oc Lithium Amidotrihydroborate Neopentyllithium (21.4 mg, 0.274 mmol, 0.950 equiv) was transferred under a nitrogen atmosphere to a suspension of borane-ammonia complex (90%, 9.9 mg, 0.29 mmol, 1 equiv) in THF-d8 (850 )l.L) at 23 °C. The resulting clear solution was transferred into an NMR tube. 11 B NMR (32 MHz, THF-d8 , B(OMe) 3 reference) 8: -40.5 (LiH 2NBH 3). 11 B NMR (32 MHz, THF-d8, BF3•0E1i reference) 8: -22.2 (LiH 2 NBH 3). 13 C NMR"'(lOO MHz, THF-d8 ) 8: 31.6 (CH3 ). 219 Chapter 4 Reduction of Pseudoephedrine Amides to Form Highly Enantiomerically Enriched Aldehydes 220 Introduction The direct conversion of alkylated carboxylic acid equivalents to highly enantiomerically enriched a-substituted aldehydes is a valuable transformation in organic synthesis. Although there are isolated instances in the literature where such a transformation could be carried out in a single step/0 there was at the time of our initial report no general procedure for the direct conversion of an alkylation product to the corresponding aldehyde. 61 Reduction of Pseudoephedrine Amides to Form Aldehydes Pseudoephedrine amides can be converted directly to highly enantiomerically enriched aldehydes using Brown and Tsukamoto's lithium triethoxyaluminum hydride reagent. 62 This reagent is produced in situ from the reaction of 1 molar equivalent of lithium aluminum hydride with 1.5 molar equivalents of ethyl acetate and affords aldehydes of 90-98% ee (75-82% yield, Table . 10) from the corresponding pseudoephedrine amides. Table 10. Reduction of Pseudoephedrine Ami des with LiAlH(OEt) 3 to Form Aldehydes 0030 NJlyR OH I = CH3 R' 1) LiAIH(OEth Hexanes-THF, 0 oc 0 HAyR 2) TFA, 1 N HCI fr entry substratea R R' prod time (h) isol yield (%) isol ee (%) 1 11 12 CH3 CH3 Bn n-Bu 16 17 Bn CH 3 Bn n-Bu 19 20 n-Bu Bn Ph Et 76 77 78 79 80 81 1.0 1.1 1.2 LO 0.8 0.9 76 75b 77 80 82 80 95 98 94 97 97 90 2 3 4 5 6 aThe starting material was in all cases of;::>:99% de except 16 which was of 97% de, and 17 which was of 98% de. bYield based on capillary GC analysis. 221 In the optimum procedure, 1 equiv of a pseudoephedrine amide is added as a solution in THF to a cold (-78 °C) suspension of the lithium ttiethoxyaluminum hydtide reagent (2.3 equiv) in hexanes. The reaction mixture is wanned to 0 oc and stirred at that temperature for 0.8-1.2 h followed by quenching. The ratio of the solvents hexanes and THF was found to be an important variable; mixtures containing less than 60% by volume of hexanes led to greater degrees of over-reduction (to the primary alcohol and to the tertiary amine). In addition, the successful· generation of the alkoxyaluminum hydride reagent was found to be quite sensitive to the quality of the lithium aluminum hydride reagent According to the reaction stoichiometry, a 10% underestimation of the content of lithium aluminum hydtide results in a 40% decrease in the amount of active hydride produced. Commercial stock solutions of lithium aluminum hydride proved to be unreliable for the preparation of lithium triethoxyaluminum hydride. Optimal results were achieved when anhydrous ethyl acetate was added slowly (ca. 1-2 h) to an ice-cooled suspension of solid lithium aluminum hydride (stored and transferred under nitrogen) in anhydrous hexanes. Quenching of the reaction mixture with a dilute solution of aqueous acid (e.g., 0.5 N aqueous hydrochloric acid solution) afforded a mixture of the desired aldehyde and a pseudoephedrine aminal by-product in a ratio ranging from 1:1 to 5:1, respectively, 0 Hs ~ N~R I 0 H I. LiAIH(OEt)s ;: CHs R' -:;.__ 0 H 3 c-\:~R + I 2. H2 0, H+ CH 3 R' t TFA, IN HCI Figure 8. Generation and cleavage of pseudoephedrine aminals. 222 depending upon the substrate (Figure 8). 63 By quenching the reaction with stronger acid (10 equiv of trifluoroacetic acid in 1 N aqueous hydrochloric acid solution), complete conversion of the aminal by-product to the desired aldehyde was achieved. Only in rare instances did trace amounts of aminal (1-2%) remain after this work-up procedure. Although inappropriate for acid-sensitive substrates, this protocol was nevertheless quite effective for the preparation of a number of highly enantiomerically emiched aldehydes. Be's of 94--98% are possible, and even the highly racemization-prone aldehyde 81 was isolated in 90% ee. 223 Experimental Section General Procedures. All non-aqueous reactions were performed in flame-dried round-bottomed or modified Schlenk (Kjeldahl shape) flasks, equipped with a magnetic stirring bar and fitted with a rubber septum under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula unless otherwise noted. concentrated by rotary evaporation at -25 Torr. Organic solutions were Flash column chromatography was performed as described by Still et al. 38 employing 230-400 mesh silica geL Analytical thin-layer chromatography was performed using glass plates precoated with 0.25-mm 230400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran was distilled under nitrogen from sodium benzophenone ketyl. Dichloromethane and triethylamine were distilled under nitrogen from calcium hydride. Ethyl acetate and hexanes used in the generation of lithium triethoxyaluminum hydride were distilled from calcium hydride at 760 torr. Solvents used for flash column chromatography were reagent-grade. Instrumentation. Infrared data are presented as follows: frequency of absorption (cm-1), intensity of absorption (br =broad, s =strong, m =medium). 1H NMR spectra were recorded at 300 MHz, and 13 C. NMR spectra were recorded at 7 5 MHz; chemical shifts are expressed in parts per million tetrarnethylsilane. (8 scale) downfield from 1 H NMR chemical shifts are referenced to the signal for residual hydrogen in the NMR solvent (CHC13 : 8 7.26, C6HD 5: 8 7.15) or to tetramethylsilane. Data are presented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, m = multiplet), integration, and coupling constant in Hertz. 13 C NMR chemical shifts are referenced to the carbon signal 224 for the solvent (CDC13 : 8 77.0, C 6D 6 : 8 128.0). Mass, spectrorr;tetry was performed at the California Institute of Technology. Chiral capillary gas chromatography (GC) analysis was carried out using an Alltech Chirasil-Val chiral fused silica capillary column, UNler isothermal conditions, with a column head pressure of 17 psi. 225 1) LiAIH(OEt)s, Hexanes I THF, 0 oc 2) TFA, 1 N HCI 76% 0 ~CH3 H : CH 2 C5Hs 76 (R)-a-Methyl Benzenepropanal 7 6 A 1-L round-bottomed flask was charged with solid lithium aluminum hydride (95%, 2.95 g, 73.9 mmol, 2.30 equiv) under a nitrogen atmosphere.. The hydride was suspended in hexanes (170 mL) and the flask was immersed in an ice bath. Ethyl acetate (10.7 mL, 110 mmol, 3.41 equiv) was added by addition funnel over a period of 1.5 h, and the resulting suspension was cooled to -78 °C. A solution of amide 11 (10.0 g, 32.1 mmol, 1 equiv) in tetrahydrofuran (110 rnL) was added via cannula over 5 min and the reaction mixture was warmed to 0 °C. Mter stining for 1 h at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (25 mL, 325 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (400 mL) and the transfer was quantitated with an additional portion oftetrahydrofuran (10 mL). The resulting biphasic mixture was stirred at 23 OC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (700 rnL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 150 rnL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (250 mL). TI1e latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (100 rnL). The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (7.5% ethyl acetate-hexanes) afforded the aldehyde 76 as a colorless liquid (3.64 g, 76%). Aldehyde 76 was oxidized64 to the corresponding carboxylic acid (39) and chiral capillary 226 GC analysis of the corresponding (R)-a-methylbenzyl amide, as described for acid 39, established that aldehyde 76 was of 95% ee. 9.29 (d, 1H, J = 1.2 Hz, CHO), 6.80-7.12 (m, 5H, aromatic), 2.72 (dd, 1H, J 1 = 13.2 Hz, J 2 = 5.4 Hz, one of PhCH2 ), 2.0-2.2 (m, 2H, one of PhCH2 , CHCHO), 0.69 (d, 3H, J = 6.9 Hz, CH3). C NMR (7 5 MHz, CDCl:J o: 13 204.3, 138.7, 128.9, 128.4, 126.3, 48.0, 36.5, 13.1. FTIR (neat, cm-1): 1723 (s, C=O). HRMS (FAB): Calcd for C10 H 13 0 (MHt: 149.0966. Found: 149.0965. TLC (50% EtOAc-hexanes), R; 76: 0.63 (UV, PMA). 11: 0.22 (UV, PMA). aminal by-product: 0.70 (UV, PMA). 227 1) LiAIH(OEt)s, Hexanes I THF, 0 °C 2) TFA, 1 N HCI 75% 0 HJycHs CH2 (CH 2)2CHs 77 (R)-2-Methylhexanal77 A 100-mL round-bottomed flask was charged with solid lithium aluminum hydride (95%, 328 mg, 8.21 mmol, 2.30 equiv) under a nitrogen atmosphere. The hydride was suspended in hexanes (16 mL) and the flask was immersed in an ice bath. Ethyl acetate (1.17 mL, 12.1 mmol, 3.38 equiv) was added by syringe pump over a period of 1.5 h, and the resulting suspension was cooled to -78 °C. A solution of amide 12 (990 mg, 3.57 mmol, 1 equiv) in tetrahydrofuran (8 mL, followed by a 1-mL rinse) was added via cannula over 3 min and the reaction mixture was warmed to 0 °C. After stitTing for 1.1 h at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (2.75 mL, 36 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (45 mL) and the transfer was quantitated with an additional portion of tetrahydrofuran (2 mL). The resulting biphasic mixture was stirred at 23 OC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (30 mL). The latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (15 mL). The organic layers were combined and the resulting solution was diluted to a total volume of 200 mL with ethyl acetate. Capillary GC analysis, using the (R)-( +)-a-methylbenzyl amide of (R)-2-methylhexanoic acid as an internal standard, indicated the amount of aldehyde 77 produced was (318 mg ± 3%, 78 ± 228 3% yield). Oxidation of aldehyde 77 to the corresponding carboxylic acid ( 40), as described above for aldehyde 76, and chiral capillary GC analysis of the corresponding (R)-a-methylbenzyl amide, as described for acid 39, established that aldehyde 77 was of 98% ee. 9.27 (d, 1H, J = 1.8 Hz, CHO), 1.83 (m, 1H, COCH), 0.85-1.15 (m, 6H, CH 2 CH 2 CH2 ), 0.78 (t, 3H, J = 7.0 Hz, CH 3 CHCO), 0.75 (d, 3H, J = 7.0 Hz, CH 3 CH2). FTIR (neat, cm-1): 1729 (s, C=O). HRMS (FAB): Calcd for c;H140 CMt: 114.1045. Found: 114.1047. TLC (50% EtOAc-hexanes), R; 77: 0.78 (PMA). 12: 0.33 (UV, PMA). 229 0 1) LiAIH(OEt)s, Hexanes I THF, 0 oc HJyCH2Ph 2) TFA, 1 N HCI CHs 77% 78 CS)-a-Methyl Benzenepropanal 7 8 A 100-mL round-bottomed flask was charged with solid lithium aluminum hydride (95%, 213 mg, 5.33 mmol, 2.30 equiv) under a nitrogen atmosphere. The hydride was suspended in hexanes (13 mL) and the flask was immersed in an ice bath. Ethyl acetate (0.765 mL, 7.83 mmol, 3.38 equiv) was added by syringe pump over a period of 1.5 h, and the resulting suspension was cooled to -78 oc_ A solution of amide 16 (721 mg, 2.32 mmol, 1 equiv) in tetrahydrofuran (6 mL, followed by a 1-mL rinse) was added via cannula over 3 min and the reaction mixture was warmed to 0 °C. After stirring for 1.2 h at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (1.8 mL, 23.3 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (30 mL) and the transfer was quantitated with an additional portion of tetrahydrofuran (2 mL). The resulting biphasic mixture was stirred at 23 OC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (19 mL). The latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (10% ethyl acetate-hexanes) afforded the aldehyde 78 as a colorless liquid (263 mg, 77%). Oxidation of aldehyde 78 to the corresponding carboxylic 230 acid (42), as described above for aldehyde 76, and chiral capillary GC analysis of the corresponding (R)-a-methylbenzyl amide, as described for acid 3 9, established that aldehyde 78 was of 94% ee. Spectroscopic data were identical to those of its enantiomer, (R)-a-methyl benzenepropanal 76. 1LC (50% EtOAc-hexanes), R; 78: 0.68 (UV, PMA). 16: 0.24 (UV, PMA). aminal by-product: 0.76 (UV, PMA). 231 Oyt~J\-c~Ph OH CH 3 CH 2(CH2hCH3 17 1) LiAIH(OEt)a, Hexanes I THF, 0 oc 2) TFA, 1 N HCI 0 H~CH2Ph CH 2(CH 2)2CH3 80% 79 (S)-a- Butyl Benzenepropanal 7 9 A 100-mL round-bottomed flask was charged with solid lithium aluminum hydride (95%, 256 mg, 6.41 mmol, 2.30 equiv) under a nitrogen atmosphere. The hydride was suspended in hexanes (18 mL) and the flask was immersed in an ice bath. Ethyl acetate (0.920 mL, 9.42 mmol, 3.38 equiv) was added by syringe pump over a period of 1.5 h, and the resulting suspension was cooled to -78 °C. A solution of amide 17 (985 mg, 2.79 mmol, 1 equiv) in tetrahydrofuran (7 mL, followed by a 2-mL rinse) was added via cannula over 3 min and the reaction mixture was warmed to 0 °C. After stirring for 45 min at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (2.1 mL, 28 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (40 mL) and the transfer was quantitated with an additional portion of hexanes (5 mL). The resulting biphasic mixture was s~ed at 23 CC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (150 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (25 mL). The latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (100% hexanes ---+ 9% ethyl acetate-hexanes) afforded the aldehyde 79 as a colorless liquid (427 mg, 80%). 232 Oxidation of aldehyde 79 to the corresponding carboxylic acid ( 43), as described above for aldehyde 76, and chiral capillary GC analysis of the corresponding (R)-a-methylbenzyl amide, as described for acid 39, established that aldehyde 79 was of 97% ee. 9.34 (d, 1H, J = 2.3 Hz, CHO), 6.9-7.3 (m, 5H, aromatic), 2.71 (dd, 1H, J 1 =13.9 Hz, J2 = 7.2 Hz, one of PhCH2), 2.36 (dd, 1H, J 1 =13.9 Hz, J2 = 7.0 Hz, one of PhCH2 ), 2.22 (m, 1H, COCH), 1.31 (m, 1H, one of COCHCH2 CH2 ), 0.9-1.2 (m, 5H, one of COCHCH2 CH2 , CH3 CH2 CH2 ), 0.74 (t, 3H, J = 6.7 Hz, CH 3). 13 C NMR (75 MHz, CDClJ 8: 204.7, 138.9, 128.9, 128.5, 126.3, 53.4, 35.0, 29.0, 28.3, 22.7, 13.8. FTIR (neat, cm-1): 1726 (s, C=O). HRMS (FAB): Calcd for C 13H 18 0 (Mt: 190.1358. Found: 190.1346. 1LC (50% EtOAc-hexanes), R; 79: 0.73 (UV, PMA). 17: 0.42 (UV, PMA). aminal by-product: 0.76 (UV, PMA). 233 1) LiAIH(OEt)s, Hexanes I THF, 0 oc 2) TFA, 1 N HCI 0 H~CH 3 CH2C5Hs 82% 80 (R)-a-Buzyl Benzenepropanal8 0 A 100-mL round-bottomed flask was charged with solid lithium aluminum hydride (95%, 259 mg, 6.48 mmo1, 2.30 equiv) under a nitrogen atmosphere. The hydride was suspended in hexanes (12 mL) and the flask was immersed in an ice bath. Ethyl acetate (0.931 mL, 9.53 mmol, 3.38 equiv) was added by syringe pump over a period of 1.5 h, and the resulting suspension was cooled to -78 oc. A solution of amide 19 (996 mg, 2.82 mmol, 1 equiv) in tetrahydrofuran (6.5 mL, followed by a 1.5-mL rinse) was added via cannula over 3 min and the reaction mixture was warmed to 0 °C. Mter stirring for 45 min at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (2.2 mL, 28 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (40 mL) and the transfer was quantitated with an additional portion of hexanes (2 mL). The resulting biphasic mixture was stirred at 23 OC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (150 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 25 mL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (25 mL). The latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (100% hexanes --7 9% ethyl acetate-hexanes) afforded the aldehyde 80 as a colorless ·liquid (441 mg, 82%). 234 Oxidation of aldehyde 80 to the corresponding carboxylic acid ( 45), as described above for aldehyde 76, and chiral capillary GC analysis of the corresponding (R)-cx.-methylbenzyl amide, as described for acid 39, established that aldehyde SO was of 97% ee. Spectroscopic data were identical to those of its enantiomer, (S)-cx.-butyl benzenepropanal 79. 1LC (40% EtOAc-hexanes), R; 80: 0.73 (UV, PMA). 19: 0.27 (UV, PMA). aminal by-product: 0.79 (UV, PMA). 235 1) LiA!H(OEth, Hexanes I THF, 0 oc 2) TFA, 1 N HCI 80% CS)-a-Ethyl Benzeneacetaldehyde 81 A 100-mL round-bottomed flask was charged with solid lithium aluminum hydride (95%, 441 mg, 11.0 mmol, 2.30 equiv) under a nitrogen atmosphere. The hydride was suspended in hexanes (21 mL) and the flask was immersed in an ice bath. Ethyl acetate (1.59 mL, 16.2 mmol, 3.38 equiv) was added by syringe pump over a period of 1.5 h, and the resulting suspension was cooled to -78 °C. A solution of amide 20 (1.50 g, 4.80 mmol, 1 equiv) in tetrahydrofuran (11 mL, followed by a 3-mL rinse) was added via cannula over 3 min and the reaction mixture was warmed to 0 °C. After stirring for 55 min at 0 °C, the reaction mixture was transferred by cannula to a solution of trifluoroacetic acid (3.7 mL, 48 mmol, 10 equiv) in 1 N aqueous hydrochloric acid solution (60 mL) and the transfer was quantitated with an additional portion of hexanes (3 mL). The resulting biphasic mixture was stirred at 23 OC for 5 min, then was diluted with 1 N aqueous hydrochloric acid solution (100 mL) and the layers were separated. The aqueous layer was extracted with ethyl acetate (3 x 20 mL) and the combined organic layers were neutralized by the cautious addition of saturated aqueous sodium bicarbonate solution (40 mL). The latter addition sometimes produced an emulsion that could be cleared by filtration through a coarse frit loaded with a 1-cm pad of Celite. The aqueous layer (pH 7-8) was separated and extracted with ethyl acetate (10 mL). The combined organic extracts were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (10% ethyl acetate-hexanes) afforded the aldehyde 81 as a colorless liquid (569 mg, 80% ). Oxidation of aldehyde 81 to the corresponding carboxylic acid ( 46), as 236 described above for aldehyde 76, and chiral capillary GC analysis of the corresponding (R)-a-methylbenzyl amide, as described for acid 3 9, established that aldehyde 81 was of 90% ee. 9.34 (d, 1H, J = 1.8 Hz, CHO), 6.8-7.15 (m, 5H, aromatic), 2.87 (m, 1H, PhCH), 1.82-1.91 (m, 1H, one of CH3CH 2), 1.48 (m, 1H, one of CH 3 CH2), 0.66 (t, 3H, 1 = 7.4 Hz, CHJ. 13 C NMR (75 MHz, CDClJ 8: 200.9, 136.2, 128.9, 128.7, 127.4, 60.7, 22.8, 11.6. FTIR (neat, cm-1): 1727 (s, C=O). HRMS (FAB): Calcd for C 10H 13 0 (MHt: 149.0966. Found: 149.0972. TLC (60% EtOAc-hexanes), R; 81: 0.79 (UV, PMA). 20: 0.45 (UV, PMA). aminal by-product: 0.82 (UV, PMA). 237 Chapter 5 Synthesis and Diastereoselective Alkylation of Cz-Symmetric Bis-amides . ' Derived from Pseudoephedrine and a Dicarboxylic Acid 238 Synthesis and Alkylation Cz-symmetric pseudoephedrine bis-amides were prepared from the commercial carboxylic acid dichlorides succinyl chloride, glutaryl chloride, adipoyl chloride, and pimeloyl chloride. Unlike the pseudoephedrine amides derived from monocarboxylic acids, these bis-amides were foams rather than crystalline solids. n= 0 n= 1 n= 2 n= 3 Pseudoephedrine succinamide (82) Pseudoephedrine glutaramide (83) Pseudoephedrine adipamide (84) Pseudoephedrine pimelamide (85) The protocol for the alkylation of these pseudoephed1ine bis-amides was similar to that for pseudoephedrine amides. The bis-amide was enolized using lithium diisopropylamide (4.2 equiv, -78 °C for 40 minutes, 0 °C for 10 minutes, and 23 °C for 3 minutes) in tetrahydrofuran in the presence of 10-12 equivalents of lithium chloride. Except for the special case where n = 2, alkylation reactions of pseudoephedrine bisamides proceeded in good yield at 0 OC with both benzyl bromide and methyl iodide to yield Cz-symmetric bis-alkylated products (Table 11). In each of these cases, the isolated product was found to be almost exclusively (>95%) a single species. It was not determined, however, whether the minor species was a minor diastereomer or a minor rotamer. That the alkylation product was in all cases essentially a single rotamer was surprising in that each of the starting materials exists as a complex mixture of 3 or 4 rotamers, depending on the substrate. In contrast, the alkylation of pseudoephedrine (mono) amide derivatives causes only a minor perturbation on the rotamer distribution. 239 Table 11. Alkylation of Pseudoephedrine Bis-amides LDA, LICI; R'X TIIF, 0 oc 0 0 xH0x'l'+ R' R' n R'X product yield(%) de(%) 0 Mel 86 74 >90 1 Mel 87 78 >90 1 PhCH2Br 88 81 >90 3 Mel 89 90 >90 3 PhCH2Br 90 86 >90 In the case of pseudoephedrine adipamide (n = 2), enolization was clean (by TLC) yet the alkylation reaction at 0 CC produced a number of products which could not be separated. The most likely explanation for the problematic alkylation reaction is that one of the enolate functionalities is alkylated, generating an electrophilic amide carbonyl group. Before a second alkylation can occur at the other enolate functionality, a Dieckmann-type Figure 9. adipamide. Dieckmann cyclization following the mono-alkylation of pseudoephedrine 240 cyclization65 occurs to produce a cyclopentanone derivative (Figure 9). Dieckmann cyclization does not occur for the other pseudoephedrine bis-amides because ring closure would form a 3, 4, or 6 membered ring for n = 0, 1, or 3, respectively. It is interesting to note that the alkylation diastereoselectivity does not seem to depend greatly on the length of the diacid precursor. Assuming that the basis of the selectivity in the alkylation of these C2-symmetric bis-amides is the same as that in the alkylation of pseudoephedrine (mono) amides, the alkylation of pseudoephedrine succinamide might be anticipated to occur with higher selectivity than the alkylation of pseudoephedrine glutaramide. When drawn in the extended conformation, the alkylation product of pseudoephedrine succinamide is predicted to be the 1,2-syn product The steric bias at one enolate 1t-face might mutually reinforce the steric bias at the other enolate 1t-face (matched case). When drawn in the extended conformation, the alkylation product of pseudoephedrine glutaramide, in contrast, is predicted to be the 1,3-anti product. The steric bias at one enolate 1t-face might counteract the ste1ic bias at the other enolate 1t-face (mismatched case). Thus the selectivity of alk:ylations where n is even should be higher than the selectivity of alkylations where n is odd, though it would be predicted that as n increases, the magnitude of matched or mismatched effects will diminish as more intervening methylene groups are placed between the two enolate functionalities. The magnitude of these effects does not appear to be large, for all the alkylation reactions studied appear to proceed in greater than 90% de. Cleavage of Alkylated C 2-Symmetric Bis-amides Though the most useful C2-symmetric products would likely be the products derived from the his-methylated succinamide, preliminary studies have focused on the cleavage of bis-benzylated compounds because the resulting products are much less water soluble compared to the his-methylated compounds. Cleavage experiments have been unsuccessful, and so far no reliable protocol has been found. Base-promoted hydrolysis 241 led to the formation of the monocarboxylic acid after approximately one day, but prolonged reaction times (two additional days) did not drive the reaction to the diacid. Acidic hydrolysis (18 N sulfuric acid, dioxane, reflux, one day) of the hismethylated pseudoephedrine pimelamide (83) led to hydrolysis at one terminus, and N --+ 0 acyl transfer at the other terminus. Prolonged heating led only to decomposition. Attempted reduction of the bis-benzylated pseudoephedrine glutaramide (82) to the corresponding diol with LPT or LAB also failed, instead affording tertiary amine at one terminus and unreacted amide at the other. Prolonged reaction· time drove the reaction primarily to the bis-tertiary amine by-product 242 Experimental Section General Procedures. All non-aqueous reactions were performed in flame-dried round-bottomed or modified Schlenk (Kjeldahl shape) flasks, equipped with a magnetic stirring bar and fitted with a rubber septum under a positive pressure of argon, unless otherwise noted. Air- and moisture-sensitive liquids and solutions were transferred via syringe or stainless steel cannula unless otherwise noted. concentrated by rotary evaporation at ~25 Torr. Organic solutions were Flash column chromatography was performed as described by Still et al. 38 employing 230-400 mesh silica gel. Analytical thin-layer chromatography was performed using glass plates precoated with 0.25-mm 230400 mesh silica gel impregnated with a fluorescent indicator (254 nm). Materials. Commercial reagents and solvents were used as received with the following exceptions. Tetrahydrofuran was distilled under nitrogen from sodium benzophenone ketyl. Dichloromethane, diisopropylamine, and triethylamine were distilled under nitrogen from calcium hydride. Lithium chloride was dried under vacuum at 150 CC for 24 h, then stored under a nitrogen atmosphere, or alternatively was flame-dried under vacuum immediately prior to use. Benzyl bromide and iodomethane were passed through basic alumina immediately prior to use. The molarity of n-butyllithium was determined by titration against diphenylacetic acid as an indicator (average of three determinations). 40 Solvents used for flash column chromatography were reagent-grade. Instrumentation. Infrared data are presented as follows: frequency of absorption (cm-1), intensity of absorption (br =broad, s =strong, m =medium). 1H NMR spectra were recorded at 300 MHz and 13C NMR spectra were recorded at 7 5 MHz; chemical shifts are expressed in parts per million tetramethylsilane. (8 scale) downfield from 1 H NMR chemical shifts are referenced to the signal for residual hydrogen in the NMR solvent (CHC13: 8 7.26, C 6HD5 : 8 7.15) or to tetramethylsilane (8 = 0). Data are presented as follows: chemical shift, multiplicity (br = broad, s = singlet, d = 243 doublet, t = triplet, q = quartet, qn = quintet, sx = sextet, m = multiplet), integration, and coupling constant in Hertz. 13 C NMR chemical shifts are referenced to the carbon signal for the solvent (CDC13 : o 77.0, C 6D 6 : o 128.0). Mass spectrometry was performed at the California Institute of Technology. Determination of Absolute Stereochemistry of Alkylation Products: The alkylation of C2-symmetric pseudoephedrine bis-arnides was assumed to proceed analogously to the alkylation of pseudoephedrine amide enolates, wherein the major pseudoephedrine alkylation product results from electrophilic attack on the putative Zenolate functionalities (R syn to the enolate oxygen) from the same face as the carbonbound methyl group of the nearer pseudoephedrine moiety when it is drawn in its extended conformation (see Figure 1, p. 14). 244 0 0 2 x,0-Jl.._,. . . . .I(-~+ +CI~CI 0 0 67% 82 C1S.2S)-Pseudoephedrine Succinamide 82 An ice-cooled solution of succinyl chloride (4.18 g, 27.0 mmol, 1 equiv) in dichloromethane (4D mL, followed by a 5-mL rinse) was added via cannula over 3 min to a solution of(+)-pseudoephedrine (9.58 g, 58.0 mmol, 2.15 equiv) and triethylamine (9.02 mL, 64.7 mmol, 2.40 equiv) in dichloromethane (130 mL) at 0 °C. The reaction mixture was stirred at 0 °C for 1 hour, then unreacted acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL). The resulting mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (300 mL). The organic layer was separated and extracted sequentially with half-saturated aqueous sodium bicarbonate solution (30 mL) and 3 N aqueous hydrochloric acid solution (2 x 50 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (5.5% methanol-dichloromethane) furnished pseudoephedrine succinamide 82 as a light brown foam (7.45 g, 67%). 245 (4:3:3:2 rotamer ratio) 7.2-7.5 (m, 10H, aromatic), 4.57 (m, 2H, CHOH), 4.24 (m, 2H, NC,HCH 3), 2.98 (s, 6H, NCH3 ), 2.97 (s, 6H, NCH 3 ), 2.94 (s, 6H, NCH 3 ), 2.93 (s, 6H, NCH3 ), 2.70 (m, 4H, CH2 CH2), 0.98 (m, 6H, CH 3 CHN). 13 C NMR (75 MHz, CDCl:J 0: 174.5, 174.2, 173.5, 173.2, 141.9, 141.8, 141.7' 141.6, 128.5, 128.4, 128.3, 128.0, 127.9, 127.7, 127.6, 127.1, 127.0, 126.8, 75.94, 75.87, 75.6, 75.5, 58.6, 58.3, 57.1, 56.9, 31.2, 29.5, 29.3, 28.6, 28.4, 26.89, 26.86, 15.5, 14.4. 3389 (br, m, OH), 1621 (s, C=O), 1484 (m), 1454 (m), 1407 (m), 1116 (m) 1049 (m), 735 (m), 702 (m). HRMS (FAB): Calcd for C24H 33 N2 0 4 (MHt: 413.2440. Found: 413.2434. 82: 0.27 (UV, PMA). pseudoephedrine: 0.03 (UV, PMA). 246 0 0 0 0 x~X'Jf+ +CI~CI 68% 83 (lS.2S)-PseudoC/l)hedrine Glutaramide 8 3 An ice-cooled solution of glutaryl chloride (4.59 g, 27.2 mmol, 1 equiv) in dichloromethane (40 mL, followed by a 10-mL rinse) was added via cannula over 3 min to a solution of (+)-pseudoephedrine (9.65 g, 58.4 mmol, 2.15 equiv) and triethylamine (9.08 mL, 65.2 mmol, 2.40 equiv) in dichloromethane (160 mL) at 0 °C. The reaction mixture was stirred at 0 CC for 1 hour, then unreacted acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL). The resulting mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (300 mL). The organic layer was separated and extracted sequentially with half-saturated aqueous sodium bicarbonate solution (2 x 35 mL) and 3 N aqueous hydrochloric acid solution (3 x 35 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (5.5% methanol-dichloromethane) furnished pseudoephedrine glutaramide 83 as a light brown foam (7.82 g, 68%). 247 (4:3:2:1 rotamer ratio) 7.0-7.6 (m, lOH, aromatic), 4.8-5.5 (m, 2H, OH), 4.52 (d, 2H, J = 8.9 Hz, CHOH), 4.41 (d, 2H, J = 8.9 Hz, CHOH), 3.823.94 (m, 2H, NCHCH3 ), 2.83 (s, 3H, NCH 3 ), 2.77 (s, 3H, NCH 3 ), 2.54 (s, 3H, NCH 3 ), 2.45 (s, 3H, NCH 3 ), 1.9-2.4 (m, 6H, CH 2 CH2 CH 2 ), 0.99 (d, 6H, J = 6.9 Hz, CH 3 CHN), 0.69 (d, 6H, J = 6.9 Hz, CH 3 CHN), 0.56 (d, 6H, J = 6.7 Hz, CH3 CHN), 0.51 (d, 6H, J = 6.8 Hz, CH3 CHN). 174.52, 174.47, 173.9, 173.7, 142.3, 142.0, 141.4, 128.5, 128.4, 128.2, 128.0, 127.9, 127.6, 127.5, 127.1, 127.0, 126.9, 126.7, 76.0, 75.5, 75.4, 59.4, 58.8, 56.6, 56.5, 33.7, 33.3, 32.3, 31.2, 31.13, 31.10, 26.9, 21.2, 20.5, 19.9, 15.8, 15.6, 14.5, 14.3. FTIR (neat, cm-1): 3380 (br, m, OH), 2979 (m), 2936 (m), 1618 (s, C=O), 1483 (m), 1453 (m), 1406 (m), 1265 (s), 1119 (m), 1049 (m), 1026 (m), 762 (m), 733 (m), 702 (m). HRMS (FAB): Calcd for C25H 35 N2 0 4 (MHt: 427.2597. Found: 427.2612. TLC (7.5% MeOH-C~Cl2), Rf 83: 0.20 (UV, PMA). pseudoephedrine: 0.03 (UV, PMA). 248 0 0 x~Xv+ +CI~CI 0 48% 84 ° C1S.2S)-Pseudoeyhedrine Adipamide 8 4 An ice-cooled solution of adipoyl chloride (1.82 g, 9.44 mmol, 1 equiv) in dichloromethane (30 mL, followed by a 5-mL rinse) was added via cannula over 3 min to a solution of (+)-pseudoephedrine (3.94 g, 23.9 mmol, 2.40 equiv), 4-dimethylaminopyridine (12.0 mg, 0.098 mmol, 0.01 equiv), and triethylamine (4.15 mL, 29.8 mmol, 3.00 equiv) in dichloromethane (60 mL) at 0 °C. The reaction mixture was stirred at 0 ac:; for 1 hour, then unreacted acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (10 mL). The resulting mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (30 mL) and dichloromethane (100 mL). The organic layer was separated and extracted sequentially with half-saturated aqueous sodium bicarbonate solution (10 mL) and 3 N aqueous hydrochloric acid solution (3 x 10 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue by flash column chromatography (4% methanol-dichloromethane) furnished pseudoephedrine adipamide 84 as a colorless foam (2.12 g, 48%). 1 H NMR (300 MHz, CDCl:J, 8: 249 (4:2:1 mixture of rotamers) 7.2-7.4 (m, 10H, aromatic), 4.00-4.58 (m, 4H, CHOH, NCHCH3), 2.91 (s, 6H, NCH 3), 2.89 (s, 6H, NCH 3), 2.83 (s, 6H, NCH 3), 2.2-2.4, 1.6-1.8 (m, 8H, CH2 CH 2CH2CH2), 1.07 (d, 6H, J = 6.8 Hz, CH3 CHN), 1.00 (m, 6H, CH 3 CHN). 3406 (br, s, OH), 1619 (s, C=O), 1483 (m), 1453 (m), 1407 (m), 1118 (m), 1050 (m), 702 (m). HRMS (FAB): Calcd for C26H 37 N2 0 4 (MHt: 441.2753. Found: 441.2763. TLC (15% Me0H--CH2C~), Rf 84: 0.68 (UV, PMA). pseudoephedrine: 0.05 (UV, PMA). 250 0 0 Et 3 N 0 0 +CI~CI CH2 C~,ooc ~~X~ 85 75% (1S.2S)-Pseudoephedrine Pimelamide 8 5 An ice-cooled solution of pimeloyl chloride (2.32 g, 11.8 mmol, 1 equiv) in dichloromethane (30 mL, followed by a 5-mL rinse) was added via cannula over 3 min to a solution of (+)-pseudoephedrine (4.28 g, 25,9 mmol, 2.20 equiv) and triethylamine (3.94 mL, 65.2 mmol, 2.40 equiv) in dichloromethane (80 mL) at 0 oc_ The reaction mixture was stirred at 0 °C for 1.3 h, then unreacted acid chloride was quenched by the addition of saturated aqueous sodium bicarbonate solution (5 mL). The mixture was partitioned between half-saturated aqueous sodium bicarbonate solution (10 mL) and dichloromethane (120 mL). The organic layer was separated and extracted sequentially with half-saturated aqueous sodium bicarbonate solution (10 mL) and 3 N aqueous hydrochloric acid solution (2 x 10 mL), then was dried over sodium sulfate and was concentrated. Purification of the residue was purified by flash column chromatography (4.5% methanol-dichloromethane) furnished pseudoephedrine pimelarnide 85 as a white foam (4.00 g, 75%). 251 1 H NMR (300 MHz, CDC13) 8: (2:1:1 rotamer ratio)' 7.2-7.4 (m, lOH, aromatic), 4.58 (m, 2H, CHOH), 4.41 (m, 2H, NCHCH 3), 4.03 (m, 2H, NCHCH3 ), 2.90 (s, 6H, NCH 3 ), 2.86 (s, 6H, NCH 3), 2.83 (s, 6H, NCH 3), 2.40 (m, 4H, CH2CO), 1.60 (m, 4H, COCH2 CH2), 1.38 (m, 2H, COCH2CH2CH2 ), 1.04 (d, 6H, J = 6.8 Hz, CH 3 CHN), 0.95 (d, 6H, J = 6.8 Hz, CH3 CHN). 13 C NMR (7 5 MHz, CDClJ 8: 175.2, 142.2, 128.6, 128.3, 127.6, 126.9, 126.5, 126.4, 76.4, 76.3, 75.3, 58.4, 57.8, 33.9, 33.6, 33.1, 28.8, 28.5, 24.8, 24.6, 24.4, 15.4, 14.5. 3372 (br, m, OH), 2936 (m), 1618 (s, C=O), 1482 (m), 1452 (m), 1406 (m), 1119 (m), 1052 (m), 760 (m), 733 (m), 702 (m). HRMS (FAB): Calcd for C27H 39 N2 0 4 (MHt: 455.2910. Found: 455.2904. 85: 0.57 (UV, PMA). pseudoephedrine:. 0.05 (UV, PMA). 252 LOA, LiCI; CH 3 1 ~ ~H3 0 CH3 CH3 QH THF, 0 oc ~~~N: I~ 74% 86 OH CH3 CH3 0 H r o Bis-methYlated Pseudo~hedrine Succinamide 8 6 A solution of n-butyllithium in hexanes (2.33 M, 0.890 mL, 2.08 mmol, 4.16 equiv) was added to a suspension of lithium chloride (254 mg, 6.00 mmol, 12.0 equiv) and diisopropylamine (0.319 mL, 2.28 mmol, 4.56 equiv) in tetrahydrofuran (3 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of succinamide 82 (206 mg, 0.500 mmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stirred at -78 °C for 45 min, at 0 °C for 10 min, at 23 OC for 3 min, and finally was cooled to 0 °C, whereupon iodomethane (0.125 mL, 2.00 mmol, 4.00 equiv) was added via syringe. The mixture was stirred at 0 °C for 15 minutes then was quenched by the addition of saturated aqueous ammonium chloride solution (1 mL). The mixture was partitioned between dichloromethane (20 mL) and water (90 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 15 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (70 ---7 90%) afforded hisamide 86 as a white foam (162 mg, 74%). High resolution 1H NMR analysis established that bis-amide 86 was of >90% de. 253 (20:1:1 ratio of species, * denotes minor species) 7.55 (m, 4H, aromatic), 7.0-7.3 (m, 6H, aromatic), 5.10 (br, 2H, OH), 4.80 (m, 2H, NCHCH3), 4.42 (m, 2H, CHOH), 3.00 (m, 2H, COCH), 2.91 * (s, 6H, NCH 3 ), 2.62* (s, 6H, NCH 3 ), 2.60 (s, 6H, NCH3), 1.33* (d, 6H, J = 7.0 Hz, CH 3 CHN), 0.97 (d, 6H, J = 6.4 Hz, COCHCH3), 0.74* (d, 6H, J = 6.7 Hz, CH 3CHN), 0.62 (d, 6H, J = 6.8 Hz, CH 3 CHN). C NMR (7 5 MHz, CDC~) 8: 13 178.6, 141.4, 128.5, 128.1, 127 .5, 127 .2, 127 .0, 75.8, 55.0, 41.4, 29.2, 14.5, 14.3. 3412 (br, m, OH), 2980 (m), 1618 (s, C=O), 1483 (m), 1452 (m), 1413 (m), 1279 (m), 1110 (m), 1050 (m), 757 (m), 731 (m), 702 (m). HRMS (FAB): Calcd for C26H 37N2 0 4 (MHt:44L2753. Found: 441.2750. 1LC (EtOAc), Rf 86: 0.33 (UV, PMA). 82: 0.13 (UV, PMA). 254 0 0 ><.v~X'V+ 83 LOA, LiCI; CH3 1 THF, 0 oc ~ ~H3 0 0 QHa~ ~~~~~ 78% OH CH 3 CH 3 CH3 CH3 OH 87 Bis-rnethylated Pseudoephedrine Glutararnide 8 7 A solution of n-butyllithium in hexanes (2.33 M, 0.890 rnL, 2.08 mmol, 4.16 equiv) was added to a suspension of lithium chloride (254 rng, 6.00 mmol, 12.0 equiv) and diisopropylamine (0.319 mL, 2.28 rnrnol, 4.56 equiv) in tetrahydrofuran (3 mL) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of glutaramide 83 (214 rng, -0.500 rnmol, 1 equiv) in tetrahydrofuran (2 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stirred at -78 °C for 45 min, at 0 OC for 10 min, at 23 OC for 3 min, and fmally was cooled to 0 CC whereupon iodomethane (0.125 mL, 2.00 mmol, 4.00 equiv) was added via syringe. The mixture was stirred at 0 °C for 10 minutes, then was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL). The mixture was partitioned between ethyl acetate (15 mL) and water (90 mL). The aqueous layer was separated and extracted with dichloromethane (3 x 15 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (80% ethyl acetate-hexanes) afforded bis-amide 87 as a white foam (177 mg, 78%). High resolution 1H NMR analysis established that bis-amide 87 was of >90% de. 255 (30:1:1 ratio of species,* denotes minor species) 7.6 (m, 4H, aromatic), 7.0-7.4 (m, 6H, aromatic), 5.32 (br, 2H, OH), 5.11 (m, 2H, NCHCH 3), 4.51 (m, 2H, CHOH), 3.00* (s, 6H, NCH 3), 2.77 (m, 2H, COCH), 2.56 (s, 6H, NCH3 ), 1.82 (dd, 2H, 11 = 6.1 Hz, 12 = 5.5 Hz, COCHCH2 ), 1.28* (d, 6H, J = 6.8 Hz, CH 3), 1.13* (d, 6H, J = 6.6 Hz, CH 3), 0.99 (d, 6H, J = 6.9 Hz, CH 3 ), 0.90* (d, 6H, J = 7.0 Hz, CH 3), 0.69* (d, 6H, J = 6.9 Hz, CH3 ), 0.59 (d, 6H, J = 6.9 Hz, CH 3). C NMR (7 5 MHz, CDClJ o: 13 177.0, 142.3, 128.2, 127.6, 127.2, 75.6, 55.9, 36.6, 33.1, 29.4, 17.9, 14.6. 3399 (br, m, OH), 2971 (m), 1617 (s, C=O), 1452 (m), 1315 (m), 1078 (m), 1049 (m), 912 (m), 730 (m), 702 (m). HRMS (FAB): Calcd for C27H 39N2 0 4 (MHt: 455.2910. Found: 455.2914. TLC (EtOAc), Rf 87: 0.32 (UV, PMA). 83: 0.10 (UV, PMA). 0 0 x~Xo/+ 83 LOA, LiCI; PhCH2 Br THF,0°C 81% Bis-benzylated Pseudoephedrine Glutaramide 88 A solution ofn-butyllithium in hexanes (2.33 M, 4.19 mL, 9.73 mmol, 4.16 equiv) was added to a suspension of lithium chloride (1.19 g, 28.1 mmol, 12.0 equiv) and diisopropylamine (1.50 mL, 10.7 mmol, 4.56 equiv) at -78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 oc_ A solution of glutaramide 83 (1.00 g, 2.34 mmol, 1 equiv) in tetrahydrofuran (8 mL, followed by a 1-mL rinse) was added via cannula. The reaction mixture was stirred at -78 °C for 45 min and at 0 OC for 10 min. Tetrahydrofuran (10 mL) was added to improve stirring of the thick suspension. Benzyl bromide (0.970 mL, 8.20 mmol, 3.50 equiv) was added via syringe, and the reaction mixture slowly thinned. The mixture was stirred at 0 °C for 50 min, then was quenched by the addition of saturated aqueous ammonium chloride solution (2 mL). The mixture was partitioned between ethyl acetate (40 mL) and water (200 mL). The aqueous layer was separated and extracted with ethyl acetate (2 x 40 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (48% ethyl acetate-hexanes) afforded bis-amide 88 as a white foam (1.15 g, 81 %). High resolution 1H NMR analysis established that bis-amide 88 was of>90% de. 257 7.6 (m, 4H, aromatic), 7.0-7.3 (m, 16H, aromatic), 5.37 (d, 2H, J = 4.4 Hz, OH), 5.20 (m, 2H, NCHCH 3), 4.48 (m, 2H, CHOH), 3.03 (m, 4H, PhCH2 ), 2.51 (m, 2H, COCH), 2.49 (s, 6H, NCH 3), 2.03 (m, 2H, COCHCH2), 0.47 (d, 6H, J = 6.9 Hz, CH 3 CHN). 13 C NMR (7 5 MHz, CDCl;) 8: 176.1, 141.9, 139.2, 129.0, 128.4, 128.3, 127.7. 127.5, 126.4, 75.9, 55.0, 40.9, 39.4, 33.2, 29.1, 14.5. 3406 (br, s, OH), 3062 (m), 3028 (m), 2981 (m), 2930 (m), 1623 (s, C=O), 1493 (m), 1454 (m), 1414 (m), 1312 (m), 1118 (m), 1078 (m), 1051 (m), 1027 (m), 911 (m), 758 (m), 733 (s), 701 (s). HRMS (FAB): Calcd for C39H 47N2 0 4 (MHt: 607.3536 Found: 607.3527. TLC (EtOAc), Rf 88: 0.54 (UV, PMA). 83: 0.13 (UV, PMA). 258 ~ I~' ~ X..V~'X"'+ 85 H3 0 . 0 QH3 0 NJl_W JlN~ I~ '0 G( -1 :: LOA, LiCI; Mel __TH_F_,_o_o_c_ _ HO H3C H3C CH3 CH3 OH 90% 89 Bis-methylated Pseudoephedrine Pimelamide 8 9 A solution ofn-butyllithium in hexanes (2.33 M, 0.89 mL, 2.08 mmol, 4.16 equiv) was added to a suspension of lithium chloride (254 mg, 6.00 mmol, 12.0 equiv) and diisopropylamine (0.319 mL, 2.28 mmol, 4.56 equiv) in tetrahydrofuran (3 mL) at-78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of pimelamide 85 (227 mg, 0.500 mmol, 1 equiv) in tetrahydrofuran (2.5 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stin·ed at -78 °C for 35 min, at 0 CC for 10 min, at 23 CC for 3 min, and fmally was cooled to 0 °C, whereupon iodomethane (0.125 mL, 2.00 mmol, 4.00 equiv) was added via syringe. The mixture was stirred at 0 CC for 20 min then was quenched by the addition of saturated aqueous ammonium chloride solution (1 mL). The mixture was partitioned between dichloromethane (15 mL) and water (75 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 15 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography (3.5% methanol-dichloromethane) afforded bis-amide 89 as a white foam (217 mg, 90%). High resolution 1H NMR analysis established that bis-amide 89 was of >90% de. 259 7.10--7.40 (m, 10 H, aromatic), 4.82 (m, 2H, NCHCH 3 ), 4.43 (d, 2H, J = 7.4 Hz, CHOH), 3.03 (s, 6H, NCH 3), 2.86 (m, 2H, COCH), 1.96 (m, 4H, COCHCH2), 1.36 (m, 2H, COCHCH2CH2 ), 1.10 (d, 6H, J = 6.8 Hz, CH3), 0.83 (d, 6H, J = 6.9 Hz, CH3). 13 C NMR (7 5 MHz, CDC13) 8: 178.3, 141.8, 128.5, 128.2, 128.1, 127.5, 127.3, 127.0, 126.8, 126.3, 75.5, 55.5, 35.8, 34.1, 29.8, 25.5, 18.5, 14.7. 3384 (br, m, OH), 2933 (m), 1615 (s, C=O), 1452 (m), 1410 (m), 1085 (m), 1049 (m), 701 (m). HRMS (FAB): Calcd for C29H 43 N2 0 4 (MHt: 483.3223. Found: 483.3209. 1LC (EtOAc), Rf 89: 0.32 (UV, PMA). 85: 0.10 (UV, PMA). LOA, LiCI; PhCH 2 Br THF, 0 oc 86% Bis-benzylated Pseudoephedrine Pimelamide 9 0 A solution ofn-butyllithium in hexanes (2.33 M, 0.89 mL, 2.08 mmol, 4.16 equiv) was added to a suspension of lithium chloride (0.212 g, 5.00 mmol, 10.0 equiv) and diisopropylamine (0.319 mL, 2.28 mmol, 4.56 equiv) in tetrahydrofuran (3 mL) at-78 °C. The suspension was warmed briefly to 0 °C, then was cooled to -78 °C. A solution of pseudoephedrine pimelamide 85 (227 mg, 0.500 mmol, 1 equiv) in tet:rahydrofuran (2.5 mL, followed by a 0.5-mL rinse) was added via cannula. The reaction mixture was stin·ed at-78 °C for 30 min, at 0 °C for 10 min, at 23 °C for 3 min, and finally was cooled to 0 CC whereupon benzyl bromide (0.208 mL, 1.75 mmol, 3.50 equiv) was added via syringe. The mixture was stirred at 0 °C for 10 min then was quenched by the addition of saturated aqueous ammonium chloride solution (1 mL). The mixture was partitioned between dichloromethane (15 mL) and water (75 mL). The aqueous layer was separated and extracted with dichloromethane (2 x 15 mL). The combined organic fractions were dried over sodium sulfate and were concentrated. Purification of the residue by flash column chromatography eluting with a gradient of ethyl acetate-hexanes (60 -7 65%) afforded hisamide 90 as a white foam (273 mg, 86%). High resolution 1H NMR analysis established that bis-amide 90 was of >90% de. 261 6.9-7.4 (m, 20H, aromatic), 5.18-5.28 (m, 4H, OH, NCHCH 3 ), 4.24 (m, 2H, CHOH), 3.00 (m, 4H, PhCH 2), 2.63 (m, 2H, COCH), 2.37 (s, 6H, NCH 3 ), 2.27 (m, 4H, COCHCH2 ), 1.39 (m, 2H, COCHCH2CH2 ), 0.38 (d, 6H, J = 6.9 Hz, CH 3 CHN). 13 C NMR (75 MHz, CDClJ 8: 176.8, 141.5, 139.6, 129.0, 128.2, 127.5, 127.2, 126.3, 75.3, 54.4, 43.9, 40.9, 33.5, 28.8, 24.8, 14.3. FTIR (neat, cm-1): 3402 (br, m, OH), 3027 (m), 2977 (m), 2929 (m), 1613 (s, C=O), 1493 (m), 1454 (m), 1414 (m), 1308 (m), 1266 (m), 1119 (m), 1046 (m), 757 (m), 740 (m), 701 (s). HRMS (FAB): Calcd for C41 H 51 N2 0 4 (MHt: 635.3845. Found: 635.3839. TLC (7.5% MeOH-CHzC12), Rf 90: 0.62 (UV, PMA). 85: 0.25 (UV, PMA). 262 References and Notes . 263 (1) Evans, D. A. in Asymmetric Synthesis; Morrison, J. D., Ed.; Academic Press: New York, 1984; Vol3, pp. 1-110. (b) Lutomski, K. A.; Meyers, A. L; in Asymm.etric Synthesis; Morrison, J.D.; Ed.; Academic Press: New York, 1984; Vol 3, pp. 213-274. (c) Seebach, D.; Imwinkelried, R.; Weber, T. in Modem. Synthetic Synthesis, Scheffold, R., Ed.; Springer, Berlin-Heidelberg, 1986; Vol 4, pp. 125-259. (d) Crosby, J. Tetrahedron 1991, 47, 4789. (e) Caine, D. in Comprehensive Orga11ic Synthesis; Trost, B. M.; Fleming, L, Eds.; Pergamon Press: New York, 1991, Vol 3, pp. 1-63. (2) Meyers, A. L; Knaus, G.; Kamata, K.; Ford, M. E. 1. Am. Chen1.. Soc. 1976, 98, 567. (3) (a) Evans, D. A.; Takacs, J. M. Tetrahedron Lett. 1980, 21, 4233. (b) Sonnet, P.; Heath, R. R. 1. Org. Chem. 1980, 45, 3137. (4) Kawanami, Y.; Ito, Y.; Kitagawa, T.; Taniguchi, Y.; Katsuki, T.; Yamaguchi, M. Tetrahedron Lett. 1984,25, 857. (5) For additional examples, see: (a) Davies, S. G.; Pure & Appl. Chem. 1988, 60, 13. (b) Drewes, S. E.; Malissar, D. G. S.; Roos, G. H. 0. Chen1.. Ber. 1993, 126, 2663. (c) Abiko, A.; Moriya, 0.; Filla, S. A.; Masamune, S. Angew. Chem. Int. Ed. Engl. 1995, 34, 793. (6) (a) Oppolzer, W.; Moretti, R.; Thomi, S. Tetrahedron Lett. 1989, 30, 5603. (b) For a previous camphor-derived system, see: Schmierer, R.; Grotemeier, G.; Helmchen, G.; Selim, A. Angew. Chem., Int. Ed. Engl. 1981, 20, 207. (7) (a) Evans, D. A.; Ennis, M.D.; Mathre, D. J. 1. Am. Chem. Soc. 1982, 104, 1737. (b) Mathre, D. Ph.D. Thesis, California Institute of Technology, 1985. (8) (a) Myers, A. G.; Yang, B. H.; Chen, H.; Gleason, J. L. 1. Am. Chen1.. Soc. 1994,116, 9361. (b) Myers, A. G.; Yang, B. H.; Chen, H.; McKinstry, L.; Kopecky, D. J.; Gleason, J. L., submitted for publication in 1. Am. Chen1.. Soc. (9) For the specific case of the alkylation of pseudoephedrine glycinamide and its application to the preparation of highly enantiomerically enriched a-amino acids, see: (a) 264 Myers, A. G.; Gleason, J. L.; Yoon, T.; Kung, D. W. J. Am. Chem. Soc. 1997, 119, 656. (b) Myers, A. G.; Gleason, J. L.; Yoon, T. J. Am. Chem. Soc. 1995,117, 8488. (10) For the use of the acyclic amino alcohol phenylglycinol as a chiral auxiliary, see: (a) Micouin, L.; Schanen, V.; Riche, C.; Chiaroni, A.; Quirion, J-C.; Husson, H-P. Tetrahedron Lett. 1994, 35, 7223. (b) Micouin, L.; Jullian, V.; Quirion, J-C.; Husson, H-P. Tetrahedron: Asymmetry, 1996, 7, 2839. (11) (a) Schmidt, E.; Calliess, F. W. Arch. Phann. 1912, 250, 154. (b) Mitchell, W. J. Chem Soc. 1940, 1153. (c) Brenner, M.; Huber, W. Helv. Chenz. Acta 1953, 36, 1109. (12) Myers, A. G.; Yang, B. H., submitted for publication in Org. Synth. (13) By contrast, N-acylation of oxazolidinones with carboxylic acid chlorides or anhydrides requires the use of the more pyrophoric reagent n-butyllithium. See: Gage, J. R.; Evans, D. A. Org. Synth., Call. Vol. VIII 1993, 339. (14) Myers, A. G.; Yoon, T.; Gleason, J. L. Tetrahedron Lett. 1995, 36, 4555. (15) This stands in contrast to the alkylation of the enolate derived from pseudoephedrine glycinamide (reference 9), where the selectivity of the alkylation with ethyl iodide was diminished in the absence of lithium chlmide (97% de with lithium chloride versus 82% de without lithium chloride). (16) (a) Seebach, D.; Bossler, H.; Griindler, H.; Shoda, S.-I. Helv. Chim. Acta 1991, 74, 197. (b) Miller, S. A.; Griffiths, S. L.; Seebach, D. Helv. Chinz. Acta 1993, 76, 563. (c) Bossler, H. G.; Seebach, D. Helv. Chiln. Acta 1994, 77, 1124. (17) (a) hnide enolates, by contrast, are essentially inert toward these same substrates (reference 7b). (b) The presence of lithium chloride in the reaction medium did not alter this outcome. Thus, the lithium enolate derived from the imide N-propionyl benzyloxazolidinone was found not to react with n-butyl iodide at 0 OC in the presence of 10 equiv of lithium chloride after 16 h (Myers, A. G.; Chen, H., California Institute of Technology, unpublished results). 265 (18) Fewer equivalents of the enolate can be employed. For example, alkylation of 1.3 equiv of the enolate derived from 1 with the iodide 67 at 23 CC for 21 h afforded the 1,3-syn alkylatin product 29 in 90% yield with 99:1 selectivity (cf. entry 4, Table 4). (19) (a) White, J. D.; Johnson, A. T. J. Org. Chenz. 1994, 59, 3347. (b) A similar observation was made by Heathcock and co-workers: Stoermer, D.; Caron, S.; Heathcock, C. H. J. Org. Chern. 1996, 61, 9115. (20) Using procedure A, the alkylation product 11 was obtained in the same yield and with the same selectivity on both small scale (0.1 mmol of amide 1) and large scale (99 mmol of amide 1). Similarly, using procedure B, the alkylation product 29 was obtained in the same yield and with the same selectivity on both small scale (1.9 mmol of the iodide 67) and large scale (17 mmol of the iodide 67). (21) Enders, D.; Tiebes, J.; DeKirnpe, N.; Keppens, M.; Stevens, C.; Smagghe, G.; Betz, 0. J. Org. Chern. 1993, 58, 4881. (22) Nicolaou, K. C.; Yue, E. W.; LaGreca, S.; Nadin, A.; Yang, Z.; Leresche, J. E.; Tsuri, T.; Naniwa, Y.; De Riccardis, F. ·chem. Eur. J., 1995, 1, 467. (23) Decicco, C. P.; Grover, P. J. Org. Chem. 1996, 61, 3534. (24) Eyans, D. A; Dow, R. L.; Shih, T. L.; Takacs, J. M.; Zahler, R. J. Am. Chern. Soc. 1990, 112, 5290. (25) Myers, A. G.; Yang, B. H.; Chen, H.; Kopecky, D. J. Synlett, in press. (26) The iodide 67 was prepared by iodination of the corresponding alcohol, prepared in ~9% ee and 90% yield by LAB reduction (see text) of the alkylation product 11. For iodination of alcohols, see: (a) Garegg, P. J.; Samuelsson, B. J. Chenz. Soc., Perkin Trans. I 1980, 2866. (b) Lange, G. L.; Gottardo, C. Synth. Commun. 1990, 20, 1473. (27) In these and all subsequent alkylation reactions, care was taken to avoid adventitious diastereomeric enrichment upon purification and de values reported reflect those of the crude reaction mixtures. 266 1 (28) It has been noted previously that H NMR resonances for protons on the Nmethyl group anti to the carbonyl oxygen of N ,.N-dimethylformamides are shifted up field of resonances corresponding to the protons of the N-methyl group syn to the carbonyl oxygen in benzene-d6 as solvent: (a) Hatton, J. V.; Richards, R. E.; Mol. Phys., 1960, 3, 253. (b) Hatton, J. V.; Richards, R. E. Mol. Phys., 1962, 5, 139. (c) Stewart, W. E.; Siddall, T. H. Ill. Chern. Rev. 1970,5, 517. (29) Similarly problematic are the reactions with electrophiles that are both ~-alkyl branched and ~-alk:oxy substituted. These reactions are extremely slow, even at 45 OC (see ref. 8b). (30) Myers, A. G.; McKinstry, L.; Barbay, J. K., manuscript in preparation. (31) Myers, A. G.; McKinstry, L. J. Org. Chem. 1996, 61, 2428. (32) Askin, D.; Volante, R. P.; Ryan, K. M.; Reamer, R. A.; Shinkai, I. Tetrahedron Lett. 1988,29, 4245. (33) Hoffman, R. W. Chem. Rev. 1989, 89, 1841. (34) In order to arrive at these conformations, it was assumed that each observed NOB was intramolecular, and that the observed enhancement was not a composite of NOB's from two or more rapidly equilibrating conformers. (35) (a) Karplus, M. J. Chern. Phys. 1959, 30, 11. (b) Karplus, M. J. Am. Chern. Soc. 1963, 85, 2870. (36) (a) Larcheveque, M.; Ignatova, E.; Cuvigny, T. Tetrahedron Lett. 1978, 3961. (b) Larcheveque, M.; Ignatova, E.; Cuvigny, T. J. OrganOJnet. Chent. 1979, 177, 5. (37) For example, enolization of ephedrine propionamide (1 equiv) with IDA (2.1 equiv) in the presence of lithium chloride (6 equiv), as described for pseudoephedrine propionarnide, and addition of n-butyl iodide at 0 OC afforded a diastereomeric mixture of alkylation products (70% de, configuration not determined) in 90% yield after purification by flash column chromatography. 267 (38) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978,43, 2923. (39) Connor, D. S.; Klein, G. W.; Taylor, G. N.; Boeckman, R. K. Jr.; Medwid, J. B. Org. Synth., CalL VoL VI 1988, lOL (40) Kofron, W. G.; Baclawski, L. M. J. Org. Chem. 1976, 41, 1879. (41) Dale, J. A.; Dull, D. L; Mosher, H. S. J. Org. Chenz.. 1969, 34, 2543. (42) Watson, M. B.; Youngson, G. W. J. Chenz.. Soc., (c), 1968, 258. (43) In each case, an authentic sample of the minor diastereomeric alkylation product was prepared for comparative analysis (chii·al capillary GC analysis of the corresponding trirnethylsilyl ether or acetate ester). In the case of amides 15, 20, 24, and 25, diastereomeric mixtures of a-epimers were obtained by epirnerization with l.DA (5 equiv) or lithium 2,2,6,6-tetramethylpiperidide (5 equiv) in THF for 5 h at 23 °C followed by quenching with aqueous ammonium chloride solution. Each of the remaining alkylation products in Tables 3 and 4 was epirnerized by stirring the substrate with trifluoroacetic acid (10 equiv) in THF at reflux fot 1 h (effecting N -7 0 acyl transfer as well as aepirnerization), followed by neutralization with aqueous sodium bicarbonate solution at 23 °C for 24 h (causing 0-7 N acyl transfer). (44) This work was conducted by Hou Chen. For details, see: Chen, H. Ph.D. Thesis, California Institute of Technology, 1997. (45) Myers, A. G.; Yang, B. H.; Chen, H., submitted for publication in Org. Synth. (46) In each case, an authentic sample of the minor diastereomeric (R)-amethylbenzyl amide was prepared for comparative analysis. (47) (a) Uffer, H.; Schlittler, E. Helv. Chint. Acta 1948, 31, 1397. (b) Gaylord, N. G. Reductions with Complex Metal Hydrides Wiley-Interscience: New York, 1956, pp. 544-592. (c) Zabicky, J., Ed. The Chemistry of Amides Wiley-Interscience: New York, 1970, pp. 795-801. 268 (48) (a) Brown, H. C.; Heim, P. J. Am. Chent. Soc. 1964, 86, 3566. (b) Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, 441. (c) Brown, H. C.; Narasimhan, S.; Choi, Y. M. Synthesis 1981, 996. (49) Brown, H. C.; Kim, S. C. Synthesis 1977, 635. (50) Brown, H. C.; Krishnamurthy, S.; Yoon, N. M. 1. Org. Chern. 1976,41, (51) Hutchins, R. 0.; Learn, K.; El-Telbany, F.; Stercho, Y. P. J. Org. Chern. 1984, 49, 2438. (52) (a) Fisher, G. B.; Harrison, J.; Fuller, J. C.; Goralski, C. T.; Singaram, B. Tetrahedron Lett. 1992, 33, 4533. (b) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Goralski, C. T.; Singaram, B. Tetrahedron Lett. 1993, 34, 1091. (c) Fisher, G. B.; Fuller, J. C.; Harrison, J.; Alvarez, S. G.; Burkhardt, E. R.; Goralski, C. T.; Singaram, B. J. Org. Chern. 1994, 59, 6378. (53) Myers, A. G.; Yang, B. H.; Kopecky, D. J. Tetrahedron Lett. 1996, 37, 3623. (54) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21, 693. (b) Andrews, G. C.; Crawford, T. C. Tetrahedron Lett. 1980, 21, 697. (55) (a) Pross, A.; Radom, L. Tetrahedron 1980, 21, 693. (b) Armstrong, D. R.; Perkins, P. G.; Walker, G. T. J. Mol. Struct. 1985, 122, 189. (56) Srebnik, M.; Cole, T. E.; Veeraraghavan, R.; Brown, H. C. J. Org. Chern. 1989, 54, 6085. (57) Alcohol 53 was used for comparative analysis. (58) Both (R)- and (S)-Mosher ester derivatives were prepared for comparative analysis. (59) Acetate esters of the diastereomeric alcohol pairs 59 and 60, 61 and 62, 63 and 64, and 65 and 66 were separated with baseline resolution when assayed by chiral capillary GC an~ysis. 269 (60) For examples, see: (a) Meyers, A. L; Spohn, R. F.; Lindetman, R. J. J. Org. Chem. 1985, 50, 3633. (b) Chibale, K.; Warren, S. Tetrahedron Lett. 1994, 35, 3991. (61) Recently, Masamune and co-workers reported a general method for this type of transformation: see ref. 5c. (62) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 86, 1089. (63) Kraus, G. A; Taschner, J. J. Org. Chem. 1980, 45, 1175, and references therein. (64) in all cases, the pseudoephedrine aminal was diastereomer, of undetermined stereochemistry. (65) Dieckmann, W. Chem. Ber. 1894, 27, 965. found to be a single 270 Appendix. Catalog of Spectra 271 Spectroscopic Data of Compounds ~ Amides 1-34: 1H NMR, FTIR, 13 C NMR 272-339 Amides 35-37: 1H NMR, FTIR 340-342 structure X and structure Y: 1H NMR, 2-D COSY 343 Acids 39-41, 43, and 46-49: 1H NMR, FTIR 344-351 Alcohols 50-52, 54, 56-66: 1H NMR, FTIR 352-366 Iodides 67-69: 1H NMR, FTIR 367-369 Tertiary Amides 70-73: 1H NMR, FTIR 370-373 Primary Alcohols 75 and 76: 1H NMR, FTIR 374-375 Aldehydes 76, 77, 79, and 81: 1H NMR, FTIR 376-379 Bis-amides 82-90: 1H NMR, FTIR 380-388 272 H3 0 jl__cHs OH N I CH 3 1 l 10 9 8 6 108.1ei XT ~-5!~--~r-----~----.------~-----.--------~--~-----------~----------~30(}0 2500 2000 1500 1000 273 . Cl/30. N~CHs I OH CHs 1 l l>-'.11 ~--.--r- lhP .--r·· __,. .,.. I 14(1 J:'(l -r--r--r -, ·--r--r - , , - -T ..- I 10(• .. -,--r T--.- I -r ··- 1 ·r- ·r--r ,, 274 w~~CH, OH CH3 2 I J I I 1 ~-1-=..::r=r=r 0 PPM i7.72 IT ~~~----,.-----.----~----~------------~----------~--------- 400f 2000 1000 275 ~,o. N~CH3 I OH CH3 I 2 , ; :· ' !. l 200 I I I I I I I : 180 160 140 120 100 80 60 ' I I 20 0 276 w~~ l) OH CHa 3 I I 10 I I I I 9 8 7 6 I I 5 0 PPM 1De.i7 IT at.te;-------.-------.-------r------,.--------------.--~-----------.---------~ 3000 2000 1000 277 3 /. I l. t ?OU I , 1 180 I t I I 160 I I I 14U I ' I ~· n I Iilii ' ~tl 'I ,...,- 40 0 PPM 278 69.97 4000 3500 3000 2500 2000 1500 1000 279 Oyr;JLO OH CH3 4 I ·: ~. 200 1 I I 180 160 -~·-r--r·--r--·1--r 14(\ 12(1 r-r··-·T .. .,. -.-IIIII ~ 1 f\(1 '---. I J I I ?(I () PPM 280 H3 0 CH3 N~CH I OH 3 CH3 ,. 5 101.12 ST 31500 2500 2000 1500 1000 ca~ 500 281 . H3 0 CH3 N~CH3 I OH CH 3 5 ., 1 .,..,. L 1l !· ..... ~ I I I I I 180 160 140 120 100 I 1;<0 I ,. +O 60 i· "T"""P ...._...,. I 20 0 PPI-4 282 3 n1 9H~Jt::5<~~ ~1 3 OH CH 3 6 i_ I I 9 8 ~ 1 A,-.._ I I I I 7 6 5 4 \". ;; 2 3 sw.a IT i J I I 1 0 PPM 283 l 200 J. I 180 180 :-I ao I I I· ll I I 120 100 80 60 40 20 0 PPM 284 '· ' I I 10 9 8 5 6 ~ I llJ I I 4 3 v~ ~ 0 SiSI.20 IT ,. i 81.74~----~r------.------.------.---------------.---~---------r----------- 4000 2000 1~0 1000 285 00;~ OH CH 3 7 L T 200 I I I I I I I I I 180 160 140 120 100 80 60 <40 20 I 286 ~3kD . N S • I OH CH 3 8 PP/ol 99.78 ST ~.•;------,------.-----~------~------------.-----~------.-------------r ..000 2000 1000 287 OJ~JLA) : I OH CHs 8 , 288 00;LO OH CH3 9 10 9 8 7 6 5 4 0 2 3 PPM 102.512 ST I· 18.32~-.------~------r-----~-------r--------------r-~----------~---------- 2!500 2000 1000 289 ~;-CO OH CH3 9 __.....,._______,.. \,.__._,_,.._ 1 200 1 1 1 , 180 1 , 1 , 160 1 "1 1 140 1 1 _______. . ,. .__ ............ 1 1 1 ":! 120 I I 100 I HCl I .___ I ...,..JII~l:~-..v--- I I I 50 j I I I 40 I 20 I , "t 1 0 pp~ 290 Hs 0 N~OH 1 OH CH3 10 91.02 ST ~.19~,-----.------.------,-------.-------------. <4000 2000 ------------.----------1000 1500 291 Oyf'o N~OH I OH CH 3 10 I I 180 l I 160 l 140 -. ., I -.-,.-, T" ·.,--.--.--1-· 100 120 80 ~~ I 60 40 --== 20 292 I I \ll I I q 7 f< 100.i1-l n JI ~ i J I I I 57.00 J,_ ··----·,-·- . 4000 3500 .- ·,--···-· --,--··-----,----3000 2500 2000 · · - -,---i----. - - - · -,---·---1500 1000 cm-1 293 .l I 180 j II 160 140 I I 120 100 T 80 60 I I T !20 0 PPM 294 ' l I 10 9 I I I 8 7 6 -"".. Jj I I I 5 4 3 l: \J lJ I I I 2 1 0 PPM 100.32 IT ,, ., 51.0··~------~------r------,------~----------~--.---~---------,------------ 4000 2000 1000 295 296 106.06 ST 89.09~------.-------.-------,-------.--------------.---------------.---------- .woo 3000 2500 2000 1500 1000 297 Oyr•o ~CH3 N . I ; OH . CH3 CH:PCH:PsHs I 13 [l l l j I I I I I I T I 200 180 160 140 120 100 80 60 T 40 1 20 0 PPM 298 H3 0 N.J!ycHa I OH - CH3 CH2 CH2 C5H 5 14 , , , 1 8 ~ ' ':;-1-,-~,---,----.---.--,-.,..---,--;---;1----;--'' ' 7 6 5 ~J :--,--,-,~....,-,~,,.---,-,--,,,.---71-:", ' ., 3 1 1 2 1 1 , , ""·-= 1-.....,--,-.,.,~.,,...,-. 0 299 ~~.~~~~~~~~·--"'T~l 200 180 16(1 140 120 l(l(l f\0 b(! 40 ?0 0 300 ==r=;==;=r=;;==r=;==;=:;=j"'-,-=;=,:;=:::-.,-., "1 -,--, o 10 9 8 7 ,. I "'l -·r 6 -t-r l 5 IMI.70 IT 11.&1~----r-----,-----~------.-----,---------~-,.---~-------r------------~ 1100 2500 2000 1!500 301 i Cl.X30 . OH )l__,cH N 3 l ; CH3 CH 2 C0 2 t-BLJ 15 ' lt d ,....,.., 110 I no T , ' ..1. 1 , , , 1 1+0 120 ,! I I 1 1 I 100 . 1 ' I 80 ' ' ' ' I 60 ' '1 1 J.... l 1 - ' 1 20 I , , 1 0 ??M 302 ;, 10 9 8 7 5 6 4 3 0 2 72.~~-------.------~------~-------r-----------L--,---------------~------------ ~ 2500 2000 1500 1000 303 w~o iI . OH ~ I 16 II 1 200 I 1 180 1 1 I 1 160 1 1 1 14 0 1 (;:.-co I ' I 1;?() ' ' 1 101) 1 1 : HIJ 1 ' ' ll I 60 I i I ' I l 1 I ' <40 ! I 20 1 1 .. 0 ... P"" 304 ~ ~H 3 0 ~~~C~2 Ph OH CH 3 CH2 (CHz) 2 CH 3 17 101.36 ST -0.42~---.------.-----.-----.------.----------~,---~:~:------.------------.- 3000 2500 2000 1!500 1000 305 306 H3 0 N~CHs ~ I OH CH3 Me 18 I I I I I I I I I 10 9 8 7 6 5 4 3 1 b PPM ~ i ' I 48.061.---- ·----r-- ----,-·-····· -, --·- -,- ---------------- ~------- ····--- , - - - - - · - 4000 3500 3000 2500 2000 i500 iOOO ca-l 307 ~ QH3 0 .0 : OH ~~CH3 CH3 Me 18 . ...... : J i I I I I 200 150 100 50 ~~ !· I 0 PPM 308 p 10& • • ST l ~ ~ ~;I· .I I I I I I II 71.~~----.----.----.----.------~~--------~-.---------.----. 4010 ~ 1000 moo aooo 1110 -~ 309 003~ = N . _ I OH CH 3 CH3 CH2CsHs ' 19 I .' l ~ 200 I I I I I I I 180 160 1-4-0 120 100 80 60 ' _l J L I I 40 20 0 PPM 310 00;~ OH CH3 CH 2 C~3 20 10 9 8 b ~-------.------y- 3000 ~0 1000 311 n N~ H39 I <DH ::: CH 3 CH2CH3 20 HIO 160 140 120 100 80 80 40 20 0. 312 00~~ OH CH 3 Me 21 }\__ --- 9 8 5 .6 7 4 3 2 100.10 IT 3000 2!500 2000 1!500 1000 ca-t 313 Oyr;~ OH CH 3 Me 21 ! : i j J 200 II ....... u ,.' ! ,[ I I I I I I I 180 160 140 120 100 BO 60 ,[1 .L I 40 20 -- I 314 9 80.01 ST 1000 2000 1500 1000 315 Oyf'~ 0 CH 3 ~ .= CH 3 OH3 CH 2 0 6 H5 OH 22 ' . I ; ' i j .....200 ...., 180 .l 160 ... l ""' .., ··I, ...- .,~., 140 .... '!,."' ., ·--r:r;,.~, 120 JDO ~~ -, eo ' .l j~ J. J -,-·-.-r-..,,i-r.r:',..~---,:r.l :' 20 60 i· l. ...1. I 316 10 9 8 7 5 6 4 3 2 a5.~74------,.------.------~-----.--------------.--------------.----------- 4000 3000 2000 1!500 1000 ca-t 317 Jl I I I 180 160 j I I T 140 120 100 T 80 T 60 40 l... -l 20 I o :PPH 318 Oyr;JyO OH CH 3 CH 2CH=CH2 24 10 100.e2 ST 24.74~.------.r------r------,-------.-------------. .-------------.------------ 4000 3000 2SOO 2000 1000 ca-t 319 , ~'~ .,.,::; - , OH ~ N NI =.CH3 CH 2 CH=CH2 24 ' 1 -" lo..L .... _Jl .... ..,.. ""1"""1 l rJ. : '" 'T I I I I I I I 180 160 140 120 100 80 60 " J,, ..... .... ..... I 40 20 0 PPM 320 W~W OH CH 3 CH3 25 104.86 ST 2500 2000 1000 321 OY~JyQ 6H CH3 CH3 25 322 ~ ~H 3 0 ~~JlyyCH 3 OH CH3 CH3 CH 3 26 a4.81 ST i· 323 324 f0l ~H 3 _0 3 ~~~CH OH CH CH CHa 3 3 27 I ! ~ l. '·I ·--- __ 1 •. _I ----- - - - ...... · - - - -r-· - - - - · - - . . . . . . ·- ... 9 I 1 6 ~. $ ...... --~--. ___ ...,...__- ·- ---- -·· 2 1 92.13 XT ~.~4----.------.------.------r---------~-.,---------~-.------------~ca-l !500 4000 3!500 2!500 1000 2000 11500 325 ~H 3 0 ~ ~~YY'CHa OH CH3 CH 3 CHa 27 I u ll ~........,.--.!••.-·-· Ito 110 lllll l..:l "" 140 ~·· ,.. •.•••.. 130 120 n••• .... ······~··-·········· 110 100 'J JL .I: ..... p ...... ... ·-····· ., J() - ...__. _ ,l_.~ .1 , ?0 e JO 40 ]D lO _,_ IO 326 OJ3~ _ N _ :: I OH CH 3 CH3 CH3 :: :: CH3 28 J\. I _ _ ·v ·~J. -~---- ---.-..--··----""'J'~--··· 1 7 --· - --,.---- - ----r-··· -·- -·----- ---~- ..... - - . - - - - - - . - - - - - r - - - - - - 6 $ • 3 2 I ~-~~----~----------~----~--------~~----~--~--------~~ .woo 3000 21500 2000 1!500 ca-l 500 1000 327 CLt30 .o _ N~CH 3 = CH ' 3 CH = 3 CH3 = OH 28 ' ' lL 1 ' lr JJ. ~1 328 Oyr~YyyPh OH CH 3 CH3 CH3 29 · · - · - - 1 ... ~-.-.-.--.- ............... ~ .......... 9 I ~- ;-....-............. -- ........... , ...... ~. . . . . 7 6 ···-1-·- .. ~ ..... - , ................. ~ . ....,-~ ............. .,.._,.....,........ ..,-... ~~--.-,--....- ......... __, .. . S -4 3 1 I 91.36 ST ~-~J_r-----.----.-----.----~----------~----~-----.--------~ 4000 3500 3000 2500 2000 1500 1000 329 Oyr;~Ph OH CH 3 CH 3 CHs 29 I I ------~------------~·~ -----r--~······r--··-r·· . --·--··--· . . ·-·············-······---·-·······•;•·····-···········-~--- ···----,-~~---r-----·--·· 190 uo no 160 150 I"<l no· 120 110 100 90 so 10 60 so .w 30 20 to 330 ~ 9H3 0 ~~~Ph OH CH 3 CH 3 CH3 30 I. ~~i . ---- ,, \ - - - - - - - , - - - - - . . . . . - - - - - - . . . . . . , - - - - - - - r- ----~ ... - ' s 6 ~\ ' -·- ! '··------. --------.~----------r--r- 4 3 91.52~ IT ~.04.~~----~---~-----r----.---------L--~--~-------.---------~ 4000 3!500 3000 21500 2000 1!500 iOOO 331 ~ I~ I, l <?Hs 0 • ~N ~ ~ /'-._1 ~Ph 1';'( I OH CH 3 CH3 CH3 i 30 ! --···..---~·-····--·----r---------------,·--·-···'"--·-······-----·--····l···········---..---··-r-·- 190 11!0 170 160 150 1"" 130 120 110 100 90 80 70 60 50 30 20 )O 332 0-;~~Ph OH CH3 CH 3 CH3 CH3 31 I I I , ' I lv i\ A ! __j ~--.--,~·~~~~~~.' I 7 '··- .. ·~~ ...... -·· .. 6 ' ..... 4 333 00;~Ph OH CH 3 CH 3 CH 3 CH 3 31 --------··---------------~~ -----·--··~·-···········-········-·········-;---··········-·····-········ ························-·--•·········-·-·-····~·---------·-190 ISO 170 160 ISO 1-<0 130 120 110 100 90 so 70 60 so 30 20 10 334 I, '., ft_ ·- ~'iiI : ____ _1v: ~-- AJv ~l_ II I ]\ I: -- ; ~ "--· • . J jl _.,._~ ./ ae.ae IT ,. ;: m.ae~.----.~---.-----.-----.-----------.----------~--------~ 2000 1!100 335 ~ 9H3 0, . ~~~Ph OH CH 3 CH 3 CH3 CH3 32 ~~ 190 110 170 160 1$0 ........ , .......... - •• T•"•r_,. .....,. ............... , ..... u-•··~··•••••·••·••,...•-•·-•·....--•'r'.,...~!......,..~..,..,..~-.--.,·~__...,.,~~-~.......,.,~~ 14<J 130 !20 l!O !00 90 110 70 : 60 SO 4Q 30 20 10 336 ~ ~H31 /'-. ~ ~ ~~OH j( ~ ~ ~Ph CH3 CH3 CH 3 CH 3 33 I ~ 1 ·-· ' ~ !!. "-- I\ . \ ·- \_- 89.62 ST ' i· ' ~.~~.---~----------~----.-----------,----~-----.--------4000 3500 ca-l 2000 1500 1000 337 ~ ~Hs 0 ~~~Ph OH CH CH CH CH 3 3 33 !I It 190 110 170 3 3 338 I! ••••••••• 4 1 ••• -· 2 •••. :t• I 87.05 ST 56.10~------~------------~-----.-------------.----~-------,---------4000 3500 3000 2500 2000 1~0 1000 QY30 .o 339 ~ ~~Ph OH CH 3 CH 3 CH3 CH3 34 oou•p•'"''''l"'~~~..,..,.,, 190 110 170 ... ,~'I""""T,....,,,,, 160 L50 I~ •••••••••J•~·,....••••I•.,...,••.,....,.•J'''''""'''o 130 120 110 100 90 30 'I'' ,,,,,,,.,,.,., ..... r-r.,..,....••.,...,..l•••,.,.~t''''''' •-r..-. .. .......,...._ 70 60 SO .tO 30 20 IO 340 10 8 9 7 6 5 4 3 o PPM 2 108.12 liT 69.38~------,-------~----~------~----------~--,-------------~------------ .rooo 3500 2000 1500 1000 341 0 HB.~ IT t I 342 ~ <[H 3 0 · ~t;J~CHz OH CH 3 CHzCBHs 37 10 8 9 7 6 5 4 3 2 106.67 ST 69.26~-----,.------r------~----~----------~--.---~--------~----------- 4000 3500 3000 2000 1500 1000 343 Me~Hc /} Mea Hb 'N Ph-1-/-0li Mec\ Ha + Oli structure Y structure X 4 6 8 0 2 " ..,. • • '· •• • ' ' •• • • 10 8 6 2 0 PPM 344 0 HO ~CH 3 :: CH2CsHs 39 J I I I I I 9 8 6 5 4 3 I 2 114.25~ n I ~ I I 11.85l·. ---.-----,-4000 3500 ···- -···--,·---1-------.,-- · · - - - - - . , - - - - - - - . - 3000 2500 2000 1500 1000 cm-1 500 345 0 HO ~CH3 ~ CH 2 (CH 2 hCH3 40 0 10 PPM 101. 63-i n ..., r. 3000 . t•• I r 2500 2000 1500 ··.-- t - ..•.. ·- 1000 CIII-1 500 346 0 HO ~CH3 ~ CH 2 0CH2 C6 Hs 41 \.. I I I I I 10 i I T i r 5 I I ~ 3 r 1 r 2 I 0 108.05 IT !: 41.414-------,-------,-------,-------.-----------~--.----7----------.------------ .woo 3000 21500 2000 11500 1000 347 0 jl_,cH2Ph HO : CH2(CH2)2¢H3 43 12 11 10 9 8 7 6 5 4 3 0 2 24.90~----.------.------.------.------,------------.-------------.-------------.- 4000 3500 3000 2500 2000 1500 1000 cm-1 500 348 =;::::;::::;:=:;::::;r:=r:::;::;=:;::::;r:=r:::;::~,'=;r==r:::;:::::r=i·--~-.-..,~ 10 6 8 9 5 ------- ..:;-..:::;::...,:;--=:;::::;::::;::::;::::;::::;:::;=;:~:::;=::;::=;::..:;=;:::::;::::::;:::: 4 3 2 0 PPI-l 98.09 n 0.201 1 3500 -. I T 3000 2500 r· . 2000 ., . 1 ·- 1500 1000 CIII-l 500 ,- 349 0 HO~CH3 CH3 CH3 47 0 0 102.45 ST 3500 2500 2000 1500 1000 PPM 350 0 HO~CH3 CH3 CH3 48 0 0 94.79 ST 3500 3000 2500 2000 1500 1000 351 / 0 HOAyyoH CH 3 0 49 I I I I I I I I 9 8 7 6 5 4 3 2 0 107.66 ST 33.17~------.-------.-------.------.---------------.----~--------.--------------- 4000 3500 3000 2500 2000 1500 1000 352 HO ~CH 3 ~ CH 2 C6 H5 50 10 111.151 n 20.39~------~----~------.------.------------,.------------.-------------~----- .4000 2f500 2000 1!500 1000 353 HO~CHs CH2(CH2hCHs 51 10 9 8 7 6 .woo 3500 3000 2500 2000 s 4 3 2 0 1000 !500 100.41 ST 1500 ca-t 354 HO~CH3 CH20CH2C 6 Hs 52 I ___ _,__; I. ,.. -- _A-- L__..'l. •, 4 f, PPM 102.29 ST 8.524------,.------r------~-----.--------------~----~--~---r----------- 4000 3500 3000 2000 1500 1000 355 HO~CH2 Ph CH2(CH2hCH3 54 ----------I I I I 8 7 6 5 4 3 41. 7 1 - L , - - - - - , . - - - - - , - - - - - , - - - - , - - - - - 4000 3500 3000 2500 2000 1500 10 9 I I 2 1 105.63 n 1000 0 PPM 356 HO~ 10 9 8 6 5 0 3 111.72 ST . l 13.24....1,---~---r-----r---.....-----..-----~----.-- 4000 3!500 3000 2500 2000 1!500 1000 !500 ca-t 357 CH 3 HO~CH3 CH 2 C6 H5 57 10 9 8 5 6 4 3 .Q 2 .92.15ST I I 1 1 I 3500 3000 2500 2000 1500 ·,-·- - - · - - 1000 c•- 1 358 ) r--· H3q_ CH ~3 HO : CH3 CH2 C6 H5 58 90.76 :n ',, 36.55~------.-------.--------,-------.---------------.----~---------.----------- 3500 3000 2500 2000 1500 1000 359 HO~CH 3 CH 3 CH 3 59 IL .. --~~-·-.----.---.---·--.---,---- 5 ~------- --~-- .. --.-.--.-~-- ...... - ..·-·· ........ ---"T""--.- .. 3 2 93.16 ST ~-~J______·r-----.-----~-----.----------~-----------.-----------~ 4000 3500 3000 2500 2000 1500 1000 cm-1 500 360 HO~CH 3 CH 3 CHs 60 , •• ~-- -· .......-...-.... -,.--.----..--·--·---· ~ Ii h. . -__A f l j L___ ·- -T • • .,. ...... ' • ' •· T .-,.-__,.... • -. ---~~··-:z;------------..--~ I 93.06 n 19.37~-----,,------r------,------,-------------.--------------.----------- 4000 3500 3000 2500 2000 1500 1000 361 3 1 4 HO~Ph CH3 CH3 2 5 61 ____________ )_ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _ _,___jJ~tl t~ -·-·- • • 1 • -- -· -- • • ' 1 •-----·• • • • · - - • ... -• • ! . o"' • • 6 -... _,...., ... -- ..·- ---·· . . . . ... • 3 ~ ... -~-·. 2 1 --- 117.09 ST --~~~r--~------. -----.--~--...-----2- 38.84...._,_J, 4000 -- 3500 3000 2500 2000 1500 1000 362 3 1 4 HO~Ph CH3 CH3 2 5 62 • .-.-.-,-....,.. ... ~,-••-rT~,_..,.·~l' • ' 9 I 7 '''6 ......... 1 ....... -. · · - ...... , .......... ~ • 5 4 ·r•-. .............. -.-. ..... ~ ............... .......-.-~~ ........ ~ 3 2 I 110.91 n 76.08~1~1-------rt------,-------.-------~---------------.l--------------.----------4000 3500 3000 2500 2000 1500 1000 cm-1 363 1 3 4 6 7 HO~Ph CH 3 CH3 CH3 2 5 8 63 ··-- -·-- -- ! I I i __ . .; -· '1 . . . . . . . . . . . . . . . . , ' ' .-•••·• , .• , .. ,_,. ..... ..- ... • I ' . , ' ' • • • ' , 3 ... ....... 2 ~ --~~ ~--,..,....-~~ l 91.39 ST .woo 3500 3000 2500 2000 1500 1000 c.-1 364 1 3 4 6 7 HO~Ph CH 3 CH 3 CHa 2 5 8 64 i I l j I ~A, JJ. - . -.... . - . · · ·· ·· · · .... - - - - - , · · · - - · rr · 1 91.61 n i' ! 42.95~r------.-------.-------.------,--------------,r--------------.---------- 4000 3500 3000 2500 2000 1500 1000 365 1 3 4 6 7 HO~Ph CH 3 CHs CHs 2 5 8 65 ~--.-~ ' .. -.-.- ............. r ...... -.. .........,......,..,,,..,....-.- ........... 1 • • • • • • • , , : · · · · • • • • · ' 7 3500 3000 s 6 .• , ... ,,_ .. ,..,.r••·•••·•,.--..-..-'1''''-...,.-,-~.-....-.-~3 2 I 93.45 n 4000 2500 2000 1500 1000 366 ! 66 · • • .. - ... , • • • • • ·- - 9 T - • • • • • - • -r· • · · · .. r · · 7 • • • • ·• • '"1 • . . . . . • 5 6 ··• • • T ·• ... , • • 92.18 n ,. i 39.38~.-------.-------.-----~.-------.---------------.-+-------------.----------- -4000 ·3500 3000 2500 2000 1500 ,, 1000 367 !~Ph CH 3 67 8 9 10 88.64 ST 41.57~-------.--------.-------.--------.----------------~--------J------,------~oo 3500 3000 2500 2000 1500 1000 368 . : - ------.----~--·,-- 9 I · ·. · ... . .-- ~- ~-· 7 ~- . ·~--- T---M··...---..-.-- · ~ 6 · •· · · · ---r·-~---·.....,...___,-----· 4 3 2 ·-· tr---... -··I 88.06 n 10.18~.------.----~.-----.------.--------------.------------.-------~-- <4000 3500 3000 2500 2000 1500 1000 369 !~Ph CH 3 CHa 69 -------·--· ---------------- :t. . ............ .,.......,. .......... -.-......,....... ................ 1-····· ....... ... ·~-.,....,....- -~~- ........ -y-.-'1' . . . . 3 I 1 90.26 n 4000 3500 3000 2500 2000 1500 1000 370 CH 3 (CH2 ) 10 CONEt2 70 ( i I- I I t L I I 1- 4 b I I I I I I 3 I I I I _j I I I I I \ 0 2 48.66~--------.-------~~-------.--------.------------------r-----------------.--------- 4000 3500 3000 2500 2000 i500 iOOO 371 CH3 (CH;0 10 CON(f.Pr) 2 71 10 9 8 7 6 5 3 4 2 109.39 ST 13.78,_------,------,,------.-------.--------~---.--------------.------------ 4000 ~0 3000 2500 2000 1500 1000 372 72 ~~~--~~T=T=T=r=r=r=c-.~-,~.~-, • .~-.~.~l~,~~~,~l~,~-:-, l ' 4 5 4 0 3 ~ 3 0 2 5 I 2 0 i -, 1 5 , rr--r· -,· , ., , ..,....-,--l.b 0 5 PPM 196.66 ST 96.64~----.------.------.------.----~r---------L--,-------------,------------~- .woo 3500 3000 2500 2000 1500 1000 373 JJ;Pr) 1 2 2 73 =r==;=::::;:::::,_.,::::::::;==;==;=;=c=;==;=T=ir=r=;::~.;:::,=;==;=T=ir=r=r==r=r--:-:--' --T ' ~-5 4 0 1 5 2 ll 3 5 1 0 0.5 91.07 n !:'· i 61.45~----.------.------.------r------.---------~-,,---~-------.-------------.- 4000 3500 3000 2ti00 2000 11500 1000 ca-l 1500 374 CH 3 (CH2)1oCH20H 74 =r~=rrT~~~=r~~=r~=rrr~=rrT~rr~=r~~rT=~~~~~~~ 9 2 8 .1 0 PP~ 85.60 n 56.97,_------.-------~------.-------.--------------.--------------~---------- 4000 3500 3000 2500 2000 1500 1000 375 Jj~H 1 2 75 ( ~I J I I I I 5,0 4.~ 4 0 3 5 I 3 I (I ? 5 I ? ~ i ~ ~ v.l__ _ I n 1 ~ 1 0 0 5 PPM: 88.07 ST 70.81~-------.-------.--------.-------~------------~-----------------,------ -4000 3e500 3000 2500 2000 ~eoo 376 0 }l_,cHs H : CH 2 CsHs 76 .---:- =;=r=;=;==r==~=r='Fi=r-;=-;-=T=-, ...:; -. I 10 9 8 7 I ' I ' ' 0 'j I t~ I 1 4 100.85 ST 9.97~r-----~r-----~-------.-------r--------------~------~----~r-----------~ 3000 1000 ca-l 377 0 H~CH3 CH2(CH2hCH3 77 8 b 109.67~ n I I I J ~-7.L.----,-----·.--· .woo 3500 3000 2!500 2000 1500 1000 cm-1 378 0 H~CH2 Ph CH2(CH:<)2CH3 79 : I' I ..;I I I 10 9 I 8 7 6 jvl.L_ '-- I I 5 4 3 I I I 2 1 0 PPM 105.56 lT ..,i i I I I l -1 j ~ ,.l_~-----.----r---~---,---------·-T--4000 3500 3000 2500 2000 1500 -.----y-·--- -----r1000 Cll-1 500 a AP 379 H w : CH 2 CH3 81 I I 9 8 I 6 ,-,-,-1-,-,-, ,-I 5 I ' 4 102.87 n 22.30 "*"------,-- --,--------r------------.-------.4000 31500 3000 2!500 2000 -.-------------.-----1500 1000 380 6 103.17 ST 2000 1!100 1000 ca-t H3 0 381 9H 3 ~ 0 N~~ t;-1 ; I OH CH 3 83 f---, 1-1 CH3 OH 'LJ_dM_ LL ,l)tJul·~ ~-~--,---,-~ 8 I > 6 I ·l I > 4 -,- 1 ··1 I 2 0 PPM 10-'.116 ST 21.18~~---------.-----.-----.----.-----------~------~---.----------.2000 1!100 1000 382 OH H3~0. N ym OHH a '-':: N . ~ I ' CHa · o CHa ~ 84 5 8 111.96 ST 23.96 J-----,----_;~--=c=---~~--~~--------~~~--------~~------:ca~-~~~~~0 1~0 .000 31500 3000 2!500 2000 1000 383 85 ~L, ' 4 3 I I "l ., I 10i5.ii ST 2000 1000 .,~., -0 384 108.72 ST 70.~~---.-----.-----.~---.-----.-----------,-----------~----------.- 21500 2000 1000 385 ~ 9H3 0 0 gH3 ~ ~~~~~ OH CH3 CH3 CH 3 CH 3 OH 87 10 0 4 6 8 PPM 1~.33 ST 3000 2000 11500 1000 ca-t !500 386 "----------''-'L_j r---r --,-----,--, --,----r-·--.--r--, -,---,- --r·---r---.-----.~J -, I 10 8 Ei 4 i '-- --,----.-~ 2 0 p p ti, 102.82 IT ~.~~----~----~----~----~-------~------------~----~--------~--------------- 1000 387 89 9 8 0 5 6 1~.22 ST 3!100 2000 il500 iOOO ca-l !500 388 I ·~ 1 PP lvl 10 ',. ~-~~------.------,,------r------,--------------T--~----------~-------L1000 <4000 1!500 2000